Revisiting Best Practices for an Accurate FFR and Non-Hyperemic Pressure Ratios (NHPR)

Recently my colleague Dr. Arnold Seto, chief of cardiology at the VA in Long Beach, California, returned from an interventional cardiology meeting in Denver where he presented a talk on innovations in coronary physiology. There were some excellent questions, but one stood out: “When is the right time to accept the fractional flow reserve (FFR) during the adenosine hyperemic recording?” I thought this issue had been settled a few years ago, but after speaking with Arnold, we thought we should revisit some of the fundamentals of FFR now that both hyperemic and resting non-hyperemic pressure ratios (NHPRs) are mainstream in the cath lab. For more detailed discussion, several recent excellent reviews on the technique, standards, pitfalls, and clinical applications of FFR have been published by both the Society for Cardiovascular Angiography and Interventions (SCAI) and European interventional cardiologists.^1-3

Starting Right: Transducers, Zeros, Connections

To begin, several critical steps are needed to ensure an accurate, reliable, and repeatable measurement as well as minimize the risk of error:

1)    Check the electric and fluid tubing connections to the recording system. For example, if there is a loose Y-connector with the Touhy-Borst valve inadequately tightened, or if the needle introducer was left in during measurement or normalization of pressures, aortic pressure would be artefactually lower (Figure 1). 

2)    Flush the fluid systems. A saline flush prior to any pressure measurement clears air bubbles, blood, and radiographic contrast from the guide catheter, reducing the risk of a damped aortic pressure waveform. Flush the pressure wire in the hoop to minimize microbubbles adhering to the pressure capsule. 

3)    Calibrate, then zero both the pressure wire and the guide catheter pressure to atmospheric pressure. Once the wire is advanced into the guide catheter, match the pressure wire signal to the guide catheter signal in the aorta after having removed the needle introducer, tightened the Y-connector, and flushed the catheter with saline. Don’t forget to anticoagulate the patient, usually with intravenous heparin. 

4)    Before the pressure wire is introduced into the patient, give intracoronary (IC) nitroglycerine (NTG) to minimize and prevent vasospasm (100-200 mcg bolus). 

5)    Advance the wire across the lesion 2-3 cm distal to the coronary lesion. The wire does not have to be placed as distal as possible and should preferably be in a segment >2.0 mm in diameter.

6)    Resting non-hyperemic pressure ratios (NHPRs) should be measured with a quiet patient after any hyperemia induced by contrast or saline flushes has abated (which may take as long as 30-45 seconds). For FFR, induce maximal hyperemia with intravenous (IV) adenosine (140 mcg/kg/min) or IC bolus of adenosine (see below).

7)    Check for signal drift after the last FFR or NHPR measurement (see below). 

Wire Signal Drift

Electronic signal offset or drift during a procedure is confirmed by checking the matching of aortic and guidewire pressures at the guide catheter before and after the measurements. On occasion, after inserting the guidewire across a lesion, a resting gradient with the aortic pressure may be noted. Several clues suggest a pressure gradient is the result of signal drift: 1) distal pressure is higher than aortic pressure; 2) the distal pressure signal is unstable and continues to drift higher or lower (Figure 2); or 3) distal pressure is lower than aortic pressure, but retains the identical waveform characteristics, including the dicrotic notch. A significant stenosis acts like a high frequency filter and obscures transmission of high frequency signals responsible for the dicrotic notch in the aortic pressure. Therefore, when a translesional pressure gradient is present, but pressure recordings are identical in shape, signal drift should be suspected. 

For piezo resistive transducers, signal drift occurs most commonly with disconnection and reconnection of the wire, especially after percutaneous coronary intervention (PCI), as any moisture on the connectors will change the electrical signal quality. For optical fiber sensors, drift occurs less frequently than with piezoelectric sensors, because moisture or blood does not interfere with the optical interface. 

Adequate Adenosine Dose?

IV adenosine has been standardized at 140 mcg/kg/min. Because of additional setup time and cost with IV adenosine, many operators prefer IC adenosine or NHPR measurements. While some question the equivalency between IV and IC doses, IC adenosine is an effective alternative to the current IV adenosine. DeBruyne B et al⁴ and other consensus statements recommend IC bolus adenosine doses of 50-100 mcg for the right coronary artery (RCA) or 100-200 mcg for the left coronary artery (LCA). Additional considerations are addressed in Table 1.

Accepting the Right FFR: Steady State or the ‘Smart’ Minimum FFR?

From Dr. Pijls’ initial publications: “FFR should be the distal coronary/arterial pressure ratio (Pd/Pa) during steady-state maximal hyperemia.”⁵ The basis for this approach is that during maximal hyperemia there is a direct relation between coronary pressure and flow, a condition best identified during a steady state of hyperemia when resistance is fixed and minimal. Common practice is to track the Pd/Pa ratio during hyperemia, wait for stable signals after a minimum of 2 minutes of infusion, and select the lowest FFR value. However, sometimes hyperemic pressure signals fluctuate due to respiration or changing venous return. Several studies have demonstrated adenosine-associated hemodynamic variability.^6-8 When should you take the FFR in an unsteady state?⁹ Here is what to do and why. 

In the DEFER and FAME studies, FFR was selected as the lowest Pd/Pa during the lowest “stable” hyperemic period. Addressing the problem of when to take FFR, Johnson N et al¹⁰ re-analyzed the original hemodynamic data from the VERIFY study. Hemodynamic tracings, obtained in duplicate, had the highest accuracy and repeatability using an automated FFR algorithm, which was the minimal Pd/Pa value at any point during the infusion, called the “smart minimum” FFR (SMFFR). The SMFFR is “the lowest average Pd/Pa of 5 consecutive cardiac cycles of sufficient quality within a run of 9 consecutive quality beats”¹⁰ and was compared to FFR values obtained during stable hyperemia. The analysis by Johnson N et al¹⁰ of the 190 complete data pairs during adenosine infusion found 3 patterns of hemodynamic response: 1) A “classic”, stable pattern (sigmoid shape, 57% of responses); 2) A “humped” pattern (sigmoid with superimposed bumps, 39%); and 3) An “unusual” pattern (no particular shape, 4%). Interestingly, even in the same patient and lesion, the hemodynamic response to adenosine varied, with duplicate patterns occurring in only 41%, 24%, and 3% of the 3 patterns, respectively (Figure 3). The cause of adenosine-induced hemodynamic variation remains unknown and unpredictable. It turned out that visual identification of the lowest Pd/Pa during hyperemia could be replaced by the automated algorithm which is universally available on all of the commercial pressure wire recorders. The minimum value of Pd/Pa will be selected as the largest gradient between Pd and Pa, which should occur only during maximal hyperemia. Despite this variability, the SMFFR has excellent reproducibility and was equivalent to the results from the VERIFY and RESOLVE study core lab FFR values. The automated FFR software selects the single minimum Pd/Pa value across an entire recording. Operators should remain vigilant for artifacts from say, a hiccup or a cough, which might produce an erroneous FFR or NHPR. Operators should also consider changing the number of beats over which the FFR is averaged to 3 or 5 beats (where the machines often default to 1 beat).

Non-Hyperemic Pressure-Derived Indices 

Resting Pressure Ratio: Instantaneous Wave-free Ratio (iFR, Pd/Pa, dPR)

Resting or non-hyperemia pressure ratios such as iFR, whole cycle Pd/Pa, and recently, diastolic-only pressure ratios (dPR) avoid the confounding questions of when to take the FFR and how to do so without adenosine-related side effects. iFR is measured during a select portion of diastole, the wave-free period (WFP), when the reflected waves of cardiac contraction and relaxation are quiescent and coincident with constant microvascular resistance.¹¹ iFR requires a good electrocardiogram and proprietary software (Philips). Resting whole cycle Pd/Pa can also be used to measure lesion significance and has a high correlation with iFR.¹² A number of diastolic resting indices (dPR) are now being validated and appear equivalent to iFR.¹³ There is an 80% concordance among NHPR indices with FFR. Reproducibility of the NHPRs depends on stable cardiac rhythm (for iFR, a quality electrocardiogram [EKG] is needed), quiet respirations, and no residual hyperemia from contrast or saline flushes. 

Bottom Line

FFR and NHPRs provide simple and reliable techniques, when appropriately applied, to determine the functional significance of coronary stenoses for critical decision making. Understanding the potential technical challenges of pressure measurements and the limitations of adenosine hyperemia will prepare the operator for any unexpected findings and avoid any miscalculations.

References

1. Lotfi A, Jeremias A, Fearon WF, et al. Expert consensus statement on the use of fractional flow reserve, intravascular ultrasound, and optical coherence tomography: a consensus statement of the Society of Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv. 2014; 83: 509-518.
2. Toth GG, Johnson NP, Jeremias A, et al. Standardization of fractional flow reserve measurements. J Am Coll Cardiol. 2016: 68; 742-753. 
3. Pijls NH, Kern MJ, Yock PG, et al. Practice and potential pitfalls of coronary pressure measurement. Catheter Cardiovasc Interv. 2000; 49(1): 1-16.
4. Adjedj J, Toth GG, Johnson NP, et al. Intracoronary adenosine dose — response relationship with hyperemia. JACC Cardiovasc Interv. 2015; 8: 1422-1430.
5. Pijls NH, van Son JA, Kirkeeide RL, et al. 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; 87(4): 1354-1367.
6. Seto AH, Tehrani DM, Bharmal MI, Kern MJ. Variations of coronary hemodynamic responses to intravenous adenosine infusion: Implications for fractional flow reserve measurements. Catheter Cardiovasc Interv. 2014 Sep 1; 84(3): 416-425.
7. Tarkin JM, Nijjer S, Sen S, et al. Hemodynamic response to intravenous adenosine and its effect on fractional flow reserve assessment: results of the Adenosine for the Functional Evaluation of Coronary Stenosis Severity (AFFECTS) study. Circ Cardiovasc Interv. 2013; 6(6): 654-661.
8. Wilson RF, Wyche K, Christensen BV, et al. Effects of adenosine on human coronary arterial circulation. Circulation. 1990; 82: 1595-1606.
9. Johnson NP, Johnson DT, Kirkeeide RL, et al. Repeatability of fractional flow reserve (FFR) despite variations in systemic and coronary hemodynamics. JACC Cardiovasc Interv. 2015 Jul; 8(8): 1018-1027.
10. Kern MJ, Seto A. Selecting the right FFR in an unsteady state: keep it simple. JACC Cardiovasc Interv. 2015; 8: 1028-1030.
11. 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.
12. 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. 
13. Hwang D, Jeon KH, Lee JM et al. Diagnostic performance of resting and hyperemic invasive physiological indices to define myocardial ischemia: validation with 13N-ammonia positron emission tomography. JACC Cardiovasc Interv. 2017 Apr 24; 10(8): 751-760.

Disclosure: Dr. Kern reports he is a consultant for Abiomed, Merit Medical, Abbott Vascular, Philips Volcano, ACIST Medical, Opsens Inc., and Heartflow Inc.