Innovation Tends to “Re-Invent” Itself
What’s old is new in the cardiac catheterization laboratory, and what’s new is, well… actually, old. In 1977, Dr. Andreas Grüntzig’s coronary angioplasty balloon catheter was designed with a small pressure lumen that could measure gradients across a coronary artery stenosis as aortic pressure minus post-stenotic or distal pressure (Pa-Pd or ΔP, but the pressure ratio as Pd/Pa was yet to be developed) to overcome the severe limitation of poor quality angiography. The translesional pressure catheter could measure pre- and post-balloon angioplasty gradients gauging the physiologic success of the percutaneous transluminal coronary angioplasty (PTCA) since angiographic visualization was sub-optimal. Grüntzig (Figure 1) established that the resting pressure gradient could be used as an invasive method to grade the severity of coronary atherosclerotic lesions.
Unfortunately, the large size of the Grüntzig’s DG 4.5F dilating catheter was not accepted in clinical practice, as miniaturization of the equipment and the improvement in angiography were thought to be sufficient to replace the ΔP. However, with continued technical advances, particularly the development of an (.014-inch) angioplasty pressure wire, a new hyperemic translesional pressure ratio called fractional flow reserve (FFR) was found to be superior to resting pressure data1 and became the standard for invasive coronary stenosis hemodynamic assessment.
Coming full circle over the last decade, the use of resting non-hyperemic translesional pressure ratios (NHPRs) like the instantaneous wave-free ratio (iFR) and even the Pd/Pa have emerged. Clinical studies have demonstrated a non-inferior relationship between the iFR and FFR, and equivalency among 5 NHPRs (Figure 2).2 Now with the wide availability of both hyperemic (FFR) and NHPRs, the question becomes, how to select which ratio to use and when to use it? In addition, what does the lab do when it does not have one of the proprietary NHPRs?
A Quick Look at the Fundamentals of Hyperemic and Non-Hyperemic Pressure Ratios
FFR, the ratio of hyperemia distal/aortic pressure (Pd/Pa at hyperemia), historically has an 80-85% correlation with non-invasive stress testing.3 From the DEFER4, FAME5, and FAME 26 trials, we know that FFR-guided percutaneous revascularization is safe and leads to reduced rates of major adverse myocardial events and revascularization. Despite strong favorable clinical data, FFR adoption rates have remained low for a variety of reasons involving requirement for adenosine hyperemia, cost, time, concept acceptance, and absent physician reimbursement. The requirement for adenosine can be easily overcome with an NHPR, markedly simplifying the procedure. Indeed, this was the rationale for the development of iFR and other NHPRs: the intent to increase the uptake of coronary physiology and maximize the appropriate interventional treatment of coronary atherosclerosis.
Davies and colleagues developed and tested the instantaneous free-wave ratio, measuring the Pd/Pa over a specific portion of the diastolic period in which the resistance was low and constant. They showed a nearly 80% correspondence with FFR in a large number of single and multicenter trials (Figure 3).7 Non-inferiority to FFR was demonstrated in two large trials, DEFINE-FLAIR8 and iFR-SWEDEHEART9 in low-risk populations with mostly stable coronary artery disease. The two iFR studies also showed a reduction in cost of nearly $900 per procedure and a 50% reduction in symptoms during the physiologic assessment, since adenosine was unnecessary.
Currently, nearly every FFR wire company touts a resting index to accompany their hyperemic system. These NHPRs have demonstrated striking similarity when compared head to head in both absolute values10 (Figure 4), as well as clinical outcomes. In a recent post-hoc analysis of 115 patients with N15 ammonia positron-emission tomography (PET) studies, NHPRs showed no difference in 2-year vessel-oriented composite outcomes (a composite of cardiac death, vessel-related myocardial infarction, and vessel-related ischemia-driven revascularization) among 864 deferred vessels.11 Given the equivalency of the NHPRs, but with a somewhat limited availability and supporting data set for complex interventions, how should one proceed when in the lab?
Where to Start? Just Like Grüntzig, Start With Any Pressure Guidewire and Obtain Resting Pd/Pa
From bench data and clinical practice, we know that the currently available pressure guidewires differ in ability to navigate the coronary vasculature and cross lesions. There is also a variance of pressure signal consistency and drift. Because some NHPRs are proprietary, they can only be used with specific brands of pressure wires. When using a pressure wire from a company without an available NHPR, one can always use the Pd/Pa or contrast Pd/Pa (cFFR)12 as a starting point.
The Pd/Pa was tested with a dichotomous ischemic threshold of 0.91, and generally correlates well with FFR and iFR.11 In clinical applications, if the initial resting Pd/Pa is >0.93, the lesion can be deferred. If the resting Pd/Pa is <0.87, and there are additional clinical factors (such as symptoms), then one could proceed to stenting.
When the NHPR is Indeterminate...
Many operators may find themselves in the situation where the NHPR, specifically Pd/Pa, is in the gray zone (0.87-0.93), not clearly positive or negative. In the absence of accompanying non-invasive or clinical data to guide the crucial decision to revascularize, one proposed pathway involves moving from resting Pd/Pa to contrast FFR and finally to FFR with intravenous (IV)/intracoronary (IC) adenosine (Figure 5).
Contrast-induced (sub-maximal hyperemia) cFFR can be easily performed in any lab with a 10 cc bolus of contrast, measuring Pd/Pa at the lowest value.12 A cFFR <0.83 supports intervention. A cFFR value >0.83 permits one to defer stenting. For a cFFR in the gray zone (between 0.76 and 0.82), one should perform adenosine-induced Pd/Pa (aka FFR) with value <0.80 being used in the decision to treat the lesion. At this time, FFR remains the only index studied in complex coronary disease with the broadest body of evidence supporting its use on a routine basis.
Discordance Between Resting and Hyperemic Indices
An interesting clinical conundrum arises when the resting and the hyperemic index are discordant, meaning what do you believe when one of the two measures indicates a physiologically significant lesion and the other measure is negative? iFR/FFR discordance occurs in 20% of cases.13 Cook and colleagues found that event rates (MACE) are highest when are both values are concordantly abnormal (iFR+/FFR+), but lower event rates were found with iFR+/FFR-, iFR-/FFR+, and iFR-/FFR-. In the IRIS-FFR registry, those patients with an abnormal FFR but normal resting index (iFR-/FFR+) had higher adverse cardiac events at 3 years compared to those with normal FFR and abnormal resting index. (iFR+/FFR-). It has been shown that the disparity in cases of iFR-/FFR+ is due to high translesional flow with high coronary flow reserve (CFR). A high translesional flow can reduce the FFR to an abnormal level, but the clinical significance of this finding remains uncertain. Some speculate that NHPRs might not be as sensitive in detecting significant lesions in the right coronary artery, since phasic coronary flow in some right coronary circulations is systolic predominant, meaning that a strictly diastolic pressure ratio may not reflect the true translesional hemodynamics.
Opportunity for Better Outcomes After PCI With Post-PCI Coronary Physiology
Unlike FFR, NHPRs have not been widely studied for prognostication in the post percutaneous coronary intervention (PCI) patient. Most operators do not perform post-PCI vessel assessment. Despite using physiology to determine whether to intervene at the beginning of a procedure, it would be logical to check one’s work afterward to ensure a good result. It is noteworthy that the DEFINE-PCI study using iFR found that 25% of post PCI procedures still had an iFR <0.89, indicating some residual ischemia due to one of several reasons, including stent under expansion, edge dissection, hidden lesion, or diffuse disease.14 The post-PCI abnormal iFR rate could be reduced from 24% to 5% with further interventions.
Clinically, higher post-PCI FFR values are associated with lower major adverse cardiac events (MACE). A major reason why FFR post PCI is not performed is that the first-generation pressure wires were not durable and that signal drift over the procedure invalidated many of their final measurements. However, new, second-generation nitinol pressure guidewires with optical sensors can function as workhorse wires and overcome these limitations. More post-PCI NHPR outcome studies are needed to ascertain optimal endpoints to improve patient outcomes.
The Bottom Line
With second-generation pressure wires, interventional cardiologists can now assess more patients with complex anatomies for physiologically guided PCI. The durable and more deliverable second-generation pressure wires also permit one wire to be used for the entire case: at the beginning to assess a lesion, stenting over the same wire, and in making final FFR measurements at case conclusion.
In the absence of a proprietary NHPR, the operator can always start with Pd/Pa and follow the algorithm (Figure 5). Should the initial Pd/Pa fall within the “gray zone”, then one can move to cFFR or adenosine FFR. With more than two decades of supporting data on use of invasive coronary physiology for PCI, there is no reason to guess on the significance of angiographic stenoses, either before or after PCI.
aBaylor Scott and White, Central Texas, Assistant Professor TAMU College of Medicine, Temple, Texas; bChief of Medicine, Long Beach VA Medical Center, Long Beach, California; Associate Chief Cardiology, University of California, Irvine Medical Center, Orange, California
Disclosures: Dr. Widmer reports receiving honoraria from UpToDate and a travel grant from Philips. Dr. Kern reports that he consults and speaks for Abbott/St. Jude, Boston Scientific, Philips Volcano, ACIST Medical Systems, and Opsens Medical.
The authors can be contacted via R. Jay Widmer, MD, PhD at email@example.com.
- Pijls NH, van Son JA, Kirkeeide RL, De Bruyne B, Gould KL. Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty. Circulation. 1993 Apr; 87(4): 1354-1367.
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- Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med. 1996; 334(26): 1703-1708.
- Zimmermann FM, Ferrara A, Johnson NP, et al. Deferral vs performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial. Eur Heart J. 2015; 36: 3182-3188.
- van Nunen LX, Zimmermann FM, Tonino PA et al. Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomized controlled trial. Lancet. 2015; 386: 1853-1860.
- Xaplanteris P, Fournier S, Pijls NHJ, et al; FAME 2 Investigators. Five-year outcomes with PCI guided by fractional flow reserve. N Engl J Med. 2018 Jul 19; 379(3): 250-259.
- Jeremias A, Maehara A, Généreux P, 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. 2014 Apr 8; 63(13): 1253-1261.
- Davies JE, Sen S, Dehbi HM, et al. Use of the instantaneous wave-free ratio or fractional flow reserve in PCI. N Engl J Med. 2017 May 11; 376(19): 1824-1834.Götberg M, Christiansen EH, Gudmundsdottir IJ; iFR-SWEDEHEART Investigators. Instantaneous wave-free ratio versus fractional flow reserve to guide PCI. N Engl J Med. 2017 May 11; 376(19): 1813-1823.
- Van’t Veer M, Pijls NHJ, Hennigan B, et al. Comparison of different diastolic resting indexes to iFR: are they all equal? J Am Coll Cardiol. 2017 Dec 26; 70(25): 3088-3096.
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- Leone AM, Scalone G, De Maria G. Efficacy of contrast medium induced Pd/Pa ratio in predicting functional significance of intermediate coronary artery stenosis assessed by fractional flow reserve: insights from the RINASCI study. EuroIntervention. 2015; 11: 421-427.
- Cook CM, Jeremias A, Petraco R, et al. Fractional flow reserve/instantaneous wave-free ratio discordance in angiographically intermediate coronary stenoses: an analysis using Doppler-derived coronary flow measurements. JACC Cardiovasc Interv. 2017 Dec 26; 10(24): 2514-2524.
- Jeremias A. Blinded physiological assessment of residual ischemia after successful angiographic percutaneous coronary intervention — the DEFINE PCI trial. Presented March 17, 2019, at the 2019 American College of Cardiology Scientific Sessions, New Orleans, Louisiana.