No Stenosis Left Behind – The Holy Grail of 100% Predictive Accuracy

In order to diminish miscategorization of coronary lesions in the catheterization laboratory and further to eliminate as much as possible the potential for operator bias in choosing revascularization versus medical therapy, the use of physiologic measurements on the table has become routine in many cath labs around the country. The accepted gold-standard method of physiologic assessment is fractional flow reserve (FFR). In this technique, a pressure-sensitive guidewire is used, after adjusting transducers to be sure the pressure wire sensor sees the same pressure as the guide-catheter fluid-filled lumen, to measure the pressure distal to a lesion simultaneous with that upstream of the lesion. Once this is done in a resting state, a vasodilating agent is administered, and the pressure is remeasured under conditions of maximal hyperemia and thus maximal coronary flow.¹ This method, with the initial use of intracoronary bolus adenosine and more recently of intravenous infusions of adenosine or other vasodilators to reach a steady state, has allowed physiologic assessment of coronary lesions in multicenter trials. In these trials, outcomes of safety and efficacy have been superior using this approach of physiologic assessment versus those achieved using angiographic assessment alone in deciding which lesions must be anatomically corrected with intervention rather than treated medically.^2-4 What has been less clear has been the rate of use of the method and the tension between the time and money commitment it requires and the pressure on the cath lab and operator to “get on” with the case. A typical adenosine infusion for assessment of FFR takes at least 3 minutes, and in the FAME trial had a mean cost per patient of $222 (it should be noted that overall the FAME trial showed an economic benefit of the FFR strategy, with a cost savings over the 5-year follow-up of $2385, along with improved outcomes).⁵ It is also clear that time out required to perform FFR, and in some labs to get the adenosine from pharmacy ready for infusion, adds to the perceived disincentive to use this method. These disincentives have led to a reluctance on the part of many operators to use the method, with use in percutaneous coronary intervention reported as low as 6% in some studies.⁶ At the same time, these disincentives have propelled other methods to the fore. 

The instantaneous wave-free ratio (iFR) calculation is an ingenious method, using the wave-free diastolic period of the coronary and aortic pressure curves to look at coronary flow in the resting state, obviating the time and cost of adenosine and using the same pressure wires with a proprietary software program. Using this technique, a correlation was seen between the iFR and FFR of 0.9, with specificity, sensitivity, negative, and positive predictive values of 91%, 85%, 85%, and 91%, respectively.⁷ Nonetheless, the clinical utility of this method was questioned in the VERIFY study, which found only a weak overall correlation between iFR and FFR of 0.6 and an even weaker correlation in the clinically important range of FFRs of 0.60-0.90 of only 0.51. These investigators also found that the iFR was not in fact independent of hyperemia and changed considerably under hyperemic states.⁸ In the same issue of that publication, however, the initial investigators for the iFR approach published a study showing that iFR indeed had an excellent correlation both with FFR and with a flow/pressure measurement index called the hyperemic stenosis resistance (HSR) index, which represents a true “gold standard” and that the FFR correlation with HSR was no better than that of iFR.⁹ A third publication from Lance Gould’s group – the original investigators who advanced the transcatheter measurement of coronary flow and resistance – was published in the same issue and suggests that indeed iFR is not independent of the degree of coronary microvascular resistance, and that also iFR is biased in presenting higher levels (iFR is +0.09 higher than FFR on average) and suggesting that this showed wide limits of agreement with FFR in 17% of cases that would alter clinical management. Finally, they presented data suggesting that iFR and the plain vanilla ratio of distal coronary to aortic pressure (Pd/Pa) were equivalent in the prediction of FFR. These authors also pointed out that no perfect cutoff for iFR exists. Using an iFR range of 0.82-0.96, there was a 96% accuracy with 2% false-negatives and false-positives. If this were acceptable clinically, it would require adenosine in only 54% of patients. If one were to insist on 99% accuracy of iFR, the range would be 0.74-0.98, yielding only 0.5% false-negatives and false-positives. Using this approach, 76% of patients would require adenosine for correct diagnosis.¹⁰ Despite this controversy, further iterations of the method have led to the popular use of a hybrid approach from the ADVISE II study in which iFR cutoff points of ≤0.85 and ≥0.94 could be classified as ischemic or non-ischemic without the use of adenosine or other vasodilator infusion, but measurements inside this “gray zone” would require the use of full adenosine-mediated FFR assessment.¹¹ At the same time, interest in non-adenosine requiring approaches led to the reevaluation of the plain Pd/Pa measurements taken in the patients and stenoses in the large ADVISE registry. When these were reexamined, there was an excellent correlation between Pd/Pa and FFR, and indeed the specificity/sensitivity curves for iFR and Pd/Pa were essentially the same. The ADVISE authors calculated that the Pd/Pa ratios needed for 90% agreement with FFR lower or greater than 0.8 were ≤0.89 and ≥0.94, for 95% agreement ≤0.88 and ≥0.97, and for 100% agreement <0.81 with no upper bound for agreement with a non-ischemic FFR. Even when using this most stringent approach for a “hybrid” use of Pd/Pa and FFR, adenosine infusion could be obviated in 14% of the patients examined.¹² 

It is with this background in mind that the investigators of the study presented in this issue of the Journal of Invasive Cardiology¹³ examined the characteristics of 555 consecutive intermediate lesions interrogated at a single institution and searched for the cutoff points that would lead to a negative and positive predictive value of 100% agreement with an FFR below or above 0.8. Ammar et al found an area under the curve for specificity/sensitivity of 0.89 – substantially similar to previously published results. In this group of real-world patients and lesions at a high-volume institution, they found that there was a potential for mischaracterization of patients especially at the high end of the Pd/Pa range if ≤0.88 to >0.95 was used as the criterion, with 16 false-negatives as well as 6 false-positives at the lower end. Using a Pd/Pa lower cutoff of ≤0.86, there was 100% agreement with an FFR of <0.8, but at the higher end, a Pd/Pa of ≥1.0 was required for 100% agreement with FFR >0.8. The take-home point is that adenosine challenge could be eliminated for a Pd/Pa of <0.87 in this group, but there is no safe upper limit for the baseline ratio. 

At the end of the day, there is variability in these measurements. The authors of the current trial are to be commended for the goal of “leaving no stenosis behind” in trying to find 100% predictive accuracy. But even the FFR seen as a gold standard has variability and also may not be a perfect measurement of ischemia. When Andreas Gruentzig introduced balloon angioplasty in 1977,¹⁴ he interrogated all lesions he treated with translesional gradients before and after dilatation to be sure that dilatation was warranted and also to show that it had been effective. This was done with relatively high-profile through-lumen balloon catheters which would invariably produce a gradient if passed through even a moderate stenosis in a smallish vessel. Since that time, we have been searching for a clinically useful tool on the table to be sure of the physiologic significance of the lesions on which we propose to intervene. The current report adds to the search for the holy grail of perfect accuracy on the table in finding physiologic evidence on which to base treatment decisions in real time. Ultimately, with growing acceptance and ease of use, short adenosine infusion may not prove the deterrent it once seemed, and some form of pressure-flow measurement will likely advance to the point of gold standard.

References

1.    Pijls NH, De Bruyne B. Coronary pressure measurement and fractional flow reserve. Heart. 1998;80:539-542.

2.    Tonino PA, De Bruyne B, Pijls NH, et al; FAME Study Investigators. Fractional flow reserve vs angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360:213-224.

3.    Pijls NH, Fearon WF, Tonino PA, et al; FAME Study Investigators. Fractional flow reserve vs angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol. 2010;56:177-184.

4.    Pijls NHJ, Van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally non-significant stenoses: 5 year follow-up of the DEFER study. J Am Coll Cardiol. 2007;49:2105-2111.

5.    Fearon WF, Bornschein B, Tonino PAL, et al; for the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) Study Investigators. Economic evaluation of fractional flow reserve–guided percutaneous coronary intervention in patients with multivessel disease. Circulation. 2010;122:2545-2550.

6.    Wijns W, Kolh P, Danchin N, et al; Task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on myocardial revascularization. Eur Heart J. 2010;31:2501-2555.

7.    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;59:1392-1402. 

8.    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;61:1421-1427.

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;61:1409-1420. 

10.    Johnson NP, Kirkeeide RL, Asrress KN, et al. Does the instantaneous wave-free ratio approximate the fractional flow reserve? J Am Coll Cardiol. 2013;61:1428-1435.

11.    Escaned J, Echavarría-Pinto M, Garcia-Garcia HM, et al. Prospective assessment of the diagnostic accuracy of instantaneous wave-free ratio to assess coronary stenosis relevance: results of ADVISE II international, multicenter study (ADenosine Vasodilator Independent Stenosis Evaluation II). JACC Cardiovasc Interv. 2015;8:824-833. 

12.    Echavarría-Pinto M, van de Hoef TP, Garcia-Garcia HM, et al. Diagnostic accuracy of baseline distal-to-aortic pressure ratio to assess coronary stenosis severity: a post-hoc analysis of the ADVISE II study. JACC Cardiovasc Interv. 2015;8:834-836. 

13.    Ammar KA, Kazmi SS, Ahmad MN, et al. Use of resting non-hyperemic indices for avoidance of fractional flow reserve measurement: the goal of 100% accuracy. J Invasive Cardiol. 2016;26:265-270.

14.    Grüntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis — percutaneous transluminal coronary angioplasty. N Engl J Med. 1979;301:61-68.

From Mt. Sinai Beth Israel, New York, New York.

Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The author reports no conflicts of interest regarding the content herein.

Address for correspondence: James R. Wilentz MD, FACC, FAHA, FSCAI, Interventional Cardiology, Endovascular Intervention, Mt. Sinai Heart at Mt. Sinai Beth Israel, 10 Union Square East, Ste 5M 1, New York, NY 10003. Email: wilentz@gmail.com