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Combined use of hyperemic and non-hyperemic pressure ratios for revascularization decision-making: From the ILIAS registry

Open AccessPublished:November 10, 2022DOI:https://doi.org/10.1016/j.ijcard.2022.11.015

      Highlights

      • Abnormal pressure ratios in both non-hyperemic and hyperemic conditions portend important prognostic value for TVF at 5-year follow up.
      • Combined application of FFR and non-hyperemic Pd/Pa efficiently identifies those vessels with concordant normal resting and hyperemic pressure ratios of which long-term clinical outcomes are excellent.
      • Our data leads to hypothesize that the decision to defer revascularization should potentially be based on combined non-hyperemic and hyperemic pressure ratios, but require confirmation in prospective studies.

      Abstract

      Objective

      The aim of this study is to evaluate the diagnostic and prognostic value of non-hyperaemic Pd/Pa and to determine its additional value when combined with the gold standard hyperaemic pressure ratio (FFR) to guide revascularization.

      Methods

      In a large, multi-center, retrospective registry, we included a total of 2141 patients with a clinical indication for coronary angiography providing physiological data in 2726 vessels. A classification was made based on the FFR (cut-off value: 0.80) and non-hyperaemic Pd/Pa (cut-off value: 0.92) values and the primary outcome was target-vessel failure (TVF) at 5-year follow-up.

      Results

      Mean age was 63 ± 10.0 and 75% of the study population were men. Regression analysis showed an overall good correlation between FFR and non-hyperaemic Pd/Pa (r = 0.73, p < 0.005) and discordance was present in 17% of the vessels. Resting Pd/Pa was independently associated with TVF at 5-year follow-up (HR 0.08, 95%CI: 0.02–0.27; p < 0.005). The risk for TVF was the lowest in vessles with concordant normal pressure ratio's, with the highest risk in vessels with any abnormal pressure ratio in which revascularization was deferred. In these vessels, there was no difference in risk for TVF between the discordant and concordant abnormal values.

      Conclusion

      Abnormal pressure ratios in both non-hyperemic and hyperemic conditions portend important prognostic value. Combined application of FFR and non-hyperemic Pd/Pa efficiently identifies those vessels with concordant normal resting and hyperemic pressure ratios of which long-term clinical outcomes are excellent. These data lead to hypothesize that the decision to defer revascularization should potentially be based on combined non-hyperemic and hyperemic pressure ratios.

      Clinical trial registration

      Inclusive Invasive Physiological Assessment in Angina Syndromes Registry (ILIAS Registry), NCT04485234

      Keywords

      1. Introduction

      Physiology-guided revascularization simplifies management of patients with obstructive coronary artery disease [
      • Xaplanteris P.
      • Fournier S.
      • Pijls N.H.J.
      • et al.
      Five-year outcomes with PCI guided by fractional flow reserve.
      ,
      • Davies J.E.
      • Sen S.
      • Dehbi H.-M.
      • et al.
      Use of the instantaneous wave-free ratio or fractional flow reserve in PCI.
      ]. To date, the fractional flow reserve (FFR), calculated as the ratio of distal coronary pressure to aortic pressure at pharmacologically-induced hyperemia, remains the most frequently used index to guide revascularization. Several randomized clinical trials support FFR-guided coronary revascularization over angiographic guided therapy, and its use is recommended in contemporary clinical practice guidelines [
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • et al.
      2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC).
      ,
      • Lawton J.S.
      • Tamis-Holland J.E.
      • Bangalore S.
      • et al.
      2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines.
      ]. Nonetheless, broad utilization of FFR has been hampered due to perceived limitations of FFR, such as the need for potent vasodilating agents for its assessment, and attention has shifted towards non-hyperemic pressure ratios (NHPR) as more accessible alternatives. Several variants of NHPR have been introduced, which are all assessed in non-hyperemic conditions but differ in the time period across the cardiac cycle during which the ratio of distal coronary to aortic pressure is calculated. Diagnostic efficacy studies have shown similar diagnostic characteristics across all NHPR [
      • Kobayashi Y.
      • Johnson N.P.
      • Zimmermann F.M.
      • et al.
      Agreement of the resting distal to aortic coronary pressure with the instantaneous wave-free ratio.
      ,
      • Lee J.M.
      • Park J.
      • Hwang D.
      • et al.
      Similarity and difference of resting distal to aortic coronary pressure and instantaneous wave-free ratio.
      ,
      • Jeremias A.
      • Maehara A.
      • Généreux P.
      • et al.
      Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting P d/P a with fractional flow reserve: the RESOLVE study.
      ,
      • de Waard G.A.
      • Danad I.
      • Petraco R.
      • et al.
      Fractional flow reserve, instantaneous wave-free ratio, and resting Pd/pa compared with [15O]H2O positron emission tomography myocardial perfusion imaging: a PACIFIC trial sub-study.
      ]. Large clinical outcomes trials have been restricted to the use of the instantaneous wave-free ratio (iFR), which have documented non-inferiority of iFR-guided revascularization versus FFR-guided revascularization in terms of adverse clinical outcome [
      • Davies J.E.
      • Sen S.
      • Dehbi H.-M.
      • et al.
      Use of the instantaneous wave-free ratio or fractional flow reserve in PCI.
      ,
      • Götberg M.
      • Christiansen E.H.
      • Gudmundsdottir I.J.
      • et al.
      Instantaneous wave-free ratio versus fractional flow reserve to guide PCI.
      ]. Nonetheless, iFR and other commercially available NHPR require software from a specific vendor, potentially hampering their broad application. The ratio of non-hyperemic distal coronary pressure to non-hyperemic aortic pressure, termed non-hyperemic Pd/Pa, is an NHPR that is routinely available across all commercially available devices, and has shown excellent agreement with iFR as well as the other commercial NHPR [
      • van de Hoef T.P.
      • Lee J.M.
      • Echavarria-Pinto M.
      • et al.
      Non-hyperaemic coronary pressure measurements to guide coronary interventions.
      ]. Nevertheless, there is little scientific data on the prognostic value of non-hyperemic Pd/Pa. Moreover, it is still unclear whether there is an additional value of combined evaluation of hyperemic and non-hyperemic pressure ratios for decision-making in clinical practice. As such, we aimed to determine the long-term prognostic value for resting Pd/Pa alone and in combination with FFR for vessel-level clinical outcomes.

      2. Methods

      2.1 Study population

      The ILIAS (Inclusive Invasive Physiological Assessment in Angina Syndromes) registry is a global, multi-center initiative pooling lesion-level coronary pressure and flow data, as well as vessel-level clinical outcome data. The registry is composed of 20 expert medical institutes from the Netherlands, Korea, Japan, Spain, Denmark, Italy and the United States of America. All data were prospectively gathered between 1998 and 2018 in local study protocols. Patients whom underwent clinically indicated invasive coronary angiography and comprehensive invasive physiological assessment of at least one native coronary artery were enrolled in the registry. Patients with hemodynamic instability, significant valvular pathology and prior coronary artery bypass graft surgery were excluded. Individual patient data for pooled analysis were collected using standardized spreadsheets and a fully compliant cloud-based clinical data platform (Castor EDC, Amsterdam, The Netherlands). Standardized definitions were used for all variables. ILIAS Registry was registered at Clinicaltrials.gov (clinicaltrials.gov Identifier: NCT04485234).

      2.2 Coronary angiography and physiological assessment

      Coronary angiography was performed using standard techniques. After diagnostic coronary angiography, coronary pressure measurements were performed in non-hyperemic and hyperemic conditions. Intracoronary nitrate (100 to 200 μg) was administered before measurements. Hyperemia was induced by intravenous infusion of adenosine (140 μg/kg per min) or adenosine triphosphate (ATP) (150 μg/kg per min) through a peripheral or central vein, intracoronary bolus injection of adenosine (20-200μg), or intracoronary bolus injection of nicorandil (3 mg), according to local standards [
      • Lim W.-H.
      • Koo B.-K.
      • Nam C.-W.
      • et al.
      Variability of fractional flow reserve according to the methods of hyperemia induction.
      ]. Non-hyperemic Pd/Pa was calculated as the ratio of mean distal coronary pressure to mean aortic pressure during non-hyperemic conditions preceding induction of coronary hyperemia, and a non-hyperemic Pd/Pa ≤ 0.92 was considered abnormal [
      • Jeremias A.
      • Maehara A.
      • Généreux P.
      • et al.
      Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting P d/P a with fractional flow reserve: the RESOLVE study.
      ]. FFR was calculated as the ratio of mean distal coronary to mean aortic pressure at pharmacologicaly-induced coronary hyperemia, and an FFR ≤ 0.80 was considered abnormal.

      2.3 Treatment and clinical follow-up

      PCI was performed according to clinical practice guidelines at the time of the procedure. However, final decisions regarding revascularization were at the discretion of the operator. Clinical follow-up was obtained at outpatient clinic visits or by telephone contact to ascertain the occurrence of target vessel failure (TVF). TVF was defined as the composite of cardiac death, acute myocardial infarction not clearly attributable to a nontarget vessel, and clinically driven (urgent) revascularization of the target vessel by means of coronary artery bypass graft surgery or PCI[
      • Garcia-Garcia H.M.
      • McFadden E.P.
      • Farb A.
      • et al.
      Standardized end point definitions for coronary intervention trials: the academic research consortium-2 consensus document.
      ]. All patient-reported events were verified by evaluating hospital records or contacting the treating cardiologist or general-practitioner.

      2.4 Statistical analysis

      Data were analyzed on a per-patient basis for clinical characteristics and on a per-vessel basis for all other calculations. Normality and homogeneity of the variances were tested using Shapiro-Wilk and Levene tests. Continuous variables are presented as mean ± SD or median (first, third quartile [Q1, Q3]) and were compared with the student-t-test or Mann-Whitney U test. Categorical variables are presented as counts and percentages and were compared using Fisher exact test. Pearson correlation was used to quantify association between the FFR and resting Pd/Pa. For vessel-to-patient analyses, robust regressions with Huber-White robust standard errors were used to adjust for clustering of vessels within patients, where appropriate. The association of non-hyperemic Pd/Pa with 5-year TVF was evaluated in vessels in which revascularization was deferred using Cox proportional hazards models, adjusted for the effect of relevant clinical and angiographic characteristics (P < 0.1 for inclusion). All clinical and angiographic characteristics (Table 1) were considered as covariates. Event rates over time were visualized using the Kaplan-Meier method. The statical significance of differences in event rates between groups was assessed with unadjusted Cox proportional hazards models and are presented using hazard ratios (HR) with 95% confidence intervals (95% CI). All Cox proportional hazards models were preceded by verification of the proportional hazard assumption using Schoenfeld's residuals. A p-value <0.05 (2-sided) was considered statistically significant. The STATA version 14.0 (statacorp, College Station, Texas) software package was used for calculations.
      Table 1Baseline clinical characteristics and physiological indices.
      PatientsN = 2141
      Demographics
       Age, yrs.63 ± 10
       Male sex, %1596 (75)
      Coronary risk factors
       Hypertension, %1292 (61)
       Diabetes, %620 (29)
       Hyperlipidemia, %1435 (67)
       Positive family history, %616 (31)
       Current smoking, %491 (23)
       Prior myocardial infarction, %438 (20)
       Prior coronary intervention, %550 (29)
      Medication
       Aspirin, %1595 (74)
       Ace-inhibitor, %852 (40)
       Beta-blocker, %944 (44)
       Nitrates, %777 (36)
      Clinical diagnosis
       Stable angina1841 (86)
       NSTEMI/unstable angina262 (12)
       STEMI38 (2)
      Evaluated vessel
       LAD1456(68)
       RCA385 (18)
       RCx303 (14)
      Quantitative Coronary Angiography
       Diameter stenosis, %53,3 ± 17.7
       Lesion length,16,1 ± 11.1
      Physiological indices
       FFR0.82 ± 0.12
       Resting Pd/Pa0.92 ± 0.09
      Data presented as n (%) or mean ± standard deviation. ACE (Angiotensin Converting Enzyme), NSTEMI (non-st-eleavted myocardial infarciton, STEMI (ST-elevated myocardial infarction), FFR (Fractional Flow Reserve), Pd (Distal coronary pressure), Pa (Aortic Pressure).

      2.5 Patient and public involvement

      All patients participating in the included studies were informed about the local study protocols and gave informed consent for the use of clinical and follow-up data. There was no patient or public involvement in the construct of the registry or the drafting of the manuscript.

      3. Results

      3.1 Patient population

      A total of 2322 patients were included in the registry and underwent invasive physiological assessment in a total of 3046 vessels. Among these, 2209 patients had angiographic apparent obstructive CAD in 2808 vessels. The other vessels (without apparent CAD) were marked by the operator as reference vessels and were excluded from the analysis. In the remaining CAD population, non-hyperemic and hyperemic coronary pressure data and vessel-level follow-up was available in 2141 patients with 2726 stenosis, which formed the final study population. The key baseline characteristics are shown in Table 1. The mean age was 63 ± 10 years and 75% of the patients were men. The overall mean FFR was 0.82 ± 0.12 and mean non-hyperemic Pd/Pa was 0.92 ± 0.09.

      3.2 Agreement between FFR and Pd/Pa

      Fig. 1 A-D show the per-vessel agreement of FFR and non-hyperemic Pd/Pa across the whole study population and per investigated vessel. In the whole study population, there was an overall good correlation between FFR and non-hyperemic Pd/Pa (r = 0.73, p < 0.005). Agreement between dichotomous values of FFR (cut-off value ≤0.80) and non-hyperemic Pd/Pa (cut-off value ≤0.92) was present in 2259 out of 2726 vessels (83%). From the vessels with disagreement, 162 out of 467 vessels (35%) had normal FFR values with abnormal non-hyperemic Pd/Pa measurements, and 305 out of 467 vessels (65%) had abnormal FFR values with normal non-hyperemic Pd/Pa values. Detailed clinical and angiographic characteristics across the different discordance groups are shown in Table 2.
      Fig. 1
      Fig. 1(A – D). Scatterplot of the relationship between FFR and resting Pd/Pa and the regression analysis in the overall population (A), and per vessel (LCA (B), lcx (C) and RCA (D)).
      Table 2Baseline clinical characteristics and physiological indices across different subgroups classified by FFR and resting Pd/Pa, or revascularization.
      FFR > 0.80P-valueFFR ≤ 0.80P-valueRevascularizedP-value*
      Pd/Pa > 0.92Pd/Pa  0.92Pd/Pa > 0.92Pd/Pa  0.92
      Patient-levelN = 1028N = 131N = 133N = 158N = 691
      Demographics
       Age, yrs63 (62–64)66 (64–67)<0.00562 (61–64)63 (61–64)0.54564 (63–65)0.048
       Male sex, %72 (69–74)75 (67–82)0.16380 (73–85)82 (76–87)0.33778 (75–81)0.019
      Coronary risk factors
       Hypertension, %58 (56–62)57 (49–65)0.79557 (49–65)59 (51–66)0.47663 (59–66)0.064
       Diabetes, %26 (24–29)35 (28–44)0.02231 (24–38)26 (20−33)0.41333 (29–36)<0.005
       Hyperlipidemia, %63 (61–67)55 (47–63)0.23571 (63–78)72 (65–72)0.43969 (65–72)0.042
       Positive family history, %30 (27–32)35 (27–44)0.45731 (24–39)41 (34–49)0.39831 (27–34)0.702
       Current smoking, %22 (20–24)15 (10−21)0.01025 (19–33)23 (18–30)0.97525 (22–28)0.057
       Prior myocardial infarction, %17 (15–19)17 (12–25)0.39817 (13–25)24 (18–31)0.50624 (21–28)<0.005
       Prior coronary intervention, %29 (26–32)26 (19–34)0.97634 (26–42)27 (25–32)0.14028 (25–32)0.614
      Medication
       Aspirin, %81 (78–83)83 (75–89)0.64388 (82–93)87 (81–92)0.15989 (86–92)<0.005
       Ace-inhibitor, %41 (38–44)46 (37–54)0.39639 (32–48)48 (41–56)0.26248 (44–52)0.011
       Beta-blocker, %45 (42–48)46 (38–55)0.54147 (38–55)57 (49–64)0.75358 (54–62)<0.005
       Nitrates, %33 (30–36)48 (38–56)<0.00538 (30–46)49 (42–57)0.71536 (32–40)0.958
      Vessel-levelN = 1451N = 145N = 157N = 188N = 785
      Evaluated vessel
       LAD, %698 (48)117 (81)n/a108 (69)156 (83)n/a463 (59)n/a
       RCA,%377 (26)12 (8)n/a28 (18)15 (8)n/a149 (19)n/a
       RCx, %376 (26)26 (11)n/a21 (13)17 (9)n/a172 (22)n/a
      Quantitative analysis
       Diameter stenosis, %44.3 ± 16.649.3 ± 15.6<0.00552.3 ± 13.455.0 ± 13.80.75564 ± 15.6<0.005
       Lesion length,12.2 ± 7.916.5 ± 9.6<0.00514.5 ± 10.718.2 ± 12.60.0820.9 ± 13.4<0.005
      Physiological metrics
       FFR0.90 ± 0.050.84 ± 0.03<0.0050.76 ± 0.030.74 ± 0.060.0090.69 ± 0.13<0.005
       Resting pd./pa0.97 ± 0.020.89 ± 0.02<0.0050.94 ± 0.020.86 ± 0.03<0.0050.85<0.005
       CFR2.91 ± 1.182.66 ± 1.17<0.0052.80 ± 1.492.50 ± 1.000.032.14 ± 1.09<0.005
      FFR (Fractional Flow Reserve), Pd/Pa (Non-hyperemic ratio between distal coronary pressure((Pd) and aortic pressure (Pa), TVF (Target Vessel Failure). *P-value for difference between revascularized and non-revascularized vessels.

      3.3 Association of FFR and Pd/Pa with 5-year clinical outcomes

      Table 3 shows the absolute TVF rates across the different subgroups. During a 5-year follow-up period, a total of 211 vessels (7.7%) experienced at least one TVF. The main driver of TVF was (repeat) revascularization (5.2%). Age, gender, the presence of diabetes mellitus, a family history for CAD, a previous myocardial infarction or the use of beta-blockers or nitrates were associated with 5-year TVF in vessels where intervention was deferred after physiological assessment. After correction for these confounders, non-hyperemic Pd/Pa as a continuous variable was independently associated with 5-year TVF (HR 0.08, 95%CI: 0.02–0.27; p < 0.005). Similarly, FFR as a continuous variable was independently associated with 5-year TVF (HR 0.05, 95%CI: 0.02–0.13; p < 0.005).A sensitivity anlaysis correcting for the inclusion of multiple vessels in one patient with respect to the outcome of myocardial death did not alter the outcomes. Fig. 2A and B show the Kaplan Meier time-to-event curves for TVF for FFR and non-hyperemic Pd/Pa, respectively. Both non-hyperemic Pd/Pa as a dichotomous variable (cut-off value of ≤0.92) and FFR (cut-off value of ≤0.80) were independently associated with an increased risk for TVF (HR 2.02, 95% CI: 1.45–2.80; p < 0.005 and HR 2.53, 95%CI: 1.81–3.54, p < 0.005).
      Table 3Five-year absolute TVF rates across the different subgroups.
      TotalFFR >0.80p-valueFFR ≤0.80p-valueRevascularizedp-value*
      Pd/Pa > 0.92Pd/Pa ≤ 0.92Pd/Pa > 0.92Pd/Pa ≤ 0.92
      TVF at 5-years, N (%)211 (7.7)71 (4.89)17 (11.72)<0.00525 (15.9)26 (13.8)0.42672 (9.17)0.064
      Cardiac death70 (2.57)27 (1.86)5 (3.45)0.0207 (4.46)10 (5.32)0.31221 (2.68)0.814
      Acute myocardial infarction (target vessel)47 (1.72)13 (0.90)4 (2.76)0.3207 (4.46)18 (2.29)0.25747 (1.72)0.204
      Urgent revascularization (target vessel)142 (5.21)45 (3.10)13 (8.97)<0.00518 (11.46)17 (9.04)0.14849 (6.24)0.107
      FFR (Fractional Flow Reserve), Pd/Pa (Non-hyperemic ratio between distal coronary pressure((Pd) and aortic pressure (Pa), TVF (Target Vessel Failure). *P-value for difference between revascularized and non-revascularized vessels.
      Fig. 2
      Fig. 2(A&B). Kaplan-meier time-to-event curve for target-vessel-failure at 5-year follow-up according to FFR (cut-off: 0.80) and resting Pd/Pa (0.92) and the corresponding hazard-ratios with 95% CI based on multi-variate cox regressional analysis.

      3.4 Prognostic value of combined FFR and non-hyperemic Pd/Pa

      Fig. 3 shows the Kaplan Meier event curves (A) and estimates (B) for TVF across different subgroups defined by 1) revascularization, 2) concordant normal non-hyperemic Pd/Pa and FFR, and 3) any abnormal pressure ratio (either abnormal FFR, abnormal non-hyperemic Pd/Pa, or both). Compared to vessels with concordant normal FFR and non-hyperemic Pd/Pa, both vessels that underwent revascularization and vessels deferred from revascularization with an abnormal pressure ratio showed an increased risk for TVF at 5-year follow-up (HR 2.22; 95% CI 1.60–3.09; p < 0.005, and HR 3.16; 95% CI 2.27–4.41; p < 0.005 respectively) (Table 4a). The incidence of TVF in vessels with any abnormal pressure ratio was also higher than in vessels that underwent revascularization (HR 1.42; 95% CI 1.02–1.96: p = 0.037). Fig. 4 depicts the Kaplan Meier event curves (A) and estimates (B) for TVF with a breakdown of concordant and discordant pressure ratios in vessels in which revascularization was deferred. There was no significant difference in the risk for TVF across the three subgroups defined by abnormal non-hyperemic Pd/Pa, abnormal FFR, or both (Table 4b).
      Fig. 3
      Fig. 3(A & B). Kaplan-meier event curves (A) and event estimates with 95% confidence intervals (B) across the different subgroups defined by 1) revascularization, 2) concordant normal non-hyperemic Pd/Pa and FFR, and 3) any abnormal pressure ratio (either abnormal FFR, abnormal non-hyperemic Pd/Pa, or both).
      Table 4aCox-regression analysis for TVF at 5-year follow-up across different subgroups.
      HRStd.Err.95% CIP-ValueP-Value*
      FFR > 0.80, Pd/Pa >0.92reference
      FFR ≤ 0.80 and/or Pd/Pa ≤0.923.160.532.27–4.41<0.005reference
      Revascularized2.220.371.60–3.09<0.0050.037
      FFR (Fractional Flow Reserve), Pd/Pa (Non-hyperemic ratio between distal coronary pressure((Pd) and aortic pressure (Pa), p-values were calculated multivariate cox-regression analysis and compared to the reference group. *P-value of difference in risk between revascularized vessels against deferred vessels with either FFR ≤ 0.80, Pd/Pa ≤ 0.92 or both.
      Fig. 4
      Fig. 4(A & B). Kaplan-meier event curves (A) and event estimates with 95% confidence intervals (B) with a breakdown of concordant and discordant pressure ratios in vessels in which revascularization was deferred.
      Table 4bCox-regression analysis for TVF at 5-year follow-up across different subgroups.
      HRStd. Err.95% CIP-Value*
      FFR > 0.80, Pd/Pa >0.92reference
      FFR > 0.80, Pd/Pa ≤0.922.840.951.47–5.48<0.005
      FFR ≤ 0.80, Pd/Pa >0.922.870.781.68–4.88<0.005
      FFR ≤ 0.80, Pd/Pa ≤0.923.330.862.01–5.53<0.005
      Revascularized2.310.501.51–3.53<0.005

      4. Discussion

      In this study, we evaluated diagnostic yield and prognostic relevance of non-hyperemic Pd/Pa alone, and in combination with FFR. We documented that both FFR and non-hyperemic Pd/Pa are independently and similarly associated with TVF at 5-year follow-up. Although the majority of vessels had concordant FFR and non-hyperemic Pd/Pa values, discordant FFR and non-hyperemic Pd/Pa was present in 17% of the investigated vessels. In comparison to vessels with concordant normal FFR and non-hyperemic Pd/Pa values, all other vessels, including those vessels whom underwent revascularization, showed increased rates of TVF at 5-year follow-up. The highest risk for TVF was found in patients with any abnormal pressure ratio in whom revascularization was deferred. The combined use of non-hyperemic Pd/Pa and FFR did not further discriminate vessels at higher risk for adverse events.

      4.1 Discordance between FFR and resting Pd/Pa

      Similar to our study where 17% of vessels showed discordance between FFR and non-hyperemic Pd/Pa at their clinical cut-off values, other studies have found discordance between hyperemic and non-hyperemic pressure ratios in approximately 15–20% of the evaluated stenoses [
      • Lee J.M.
      • Park J.
      • Hwang D.
      • et al.
      Similarity and difference of resting distal to aortic coronary pressure and instantaneous wave-free ratio.
      ,
      • Ahn J.-M.
      • Park D.-W.
      • Kim S.-O.
      • et al.
      Prognostic value of resting distal-to-aortic coronary pressure in clinical practice.
      ,
      • Wijntjens G.W.M.
      • van de Hoef T.P.
      • Meuwissen M.
      • et al.
      Prognostic implications of resting distal coronary-to-aortic pressure ratio compared with fractional flow reserve: a 10-year follow-up study after deferral of revascularisation.
      ]. In comparison with independent reference standards, however, studies have repeatedly documented equivalent diagnostic efficacy between FFR and all NHPR. The origin of disagreement between FFR and NHPR therefore cannot be explained by technical differences between the methodologies, but is assumed to be multifactorial, including procedural, and physiological characteristics that drive discrepancies. These have recently been detailed elsewhere [
      • van de Hoef T.P.
      • Lee J.M.
      • Echavarria-Pinto M.
      • et al.
      Non-hyperaemic coronary pressure measurements to guide coronary interventions.
      ]. Most importantly, it is important to note the role of coronary flow and the vasodilatory capacity of the coronary circulation on the pressure drop across a stenosis. The magnitude of the pressure drop is directly correlated to the flow through it. As such, a diminished hyperemic flow – due to an abnormal vasodilatory capacity - in the presence of increased baseline flow may result into a normal FFR value and an abnormal resting Pd/Pa value. This is further.

      4.2 Prognostic value of Pd/Pa and clinical implications of combining FFR and Pd/Pa

      To our knowledge, our study is the first large registry-based study with long-term follow-up information regarding FFR, non-hyperemic Pd/Pa and the clinical implications of combining both indices. We found that resting Pd/Pa (cut-off value ≤0.92) was independently associated with TVF (HR 2.56, 95% CI: 1.68–3.89; p < 0.005) at 5-year follow-up, which was similar to FFR. Hereby, we affirm and extend previous findings by Ahn et al., describing similar rates of TVF at 2-year follow-up [
      • Ahn J.-M.
      • Park D.-W.
      • Kim S.-O.
      • et al.
      Prognostic value of resting distal-to-aortic coronary pressure in clinical practice.
      ].
      Moreover, compared to concordant normal FFR and resting Pd/Pa, all vessels with impaired FFR, non-hyperemic Pd/Pa, or both, in whom revascularization was deferred, showed an increased risk for TVF at 5-year follow-up. The TVF rate at 5-year follow-up in these vessels was also higher than that observed in vessels which underwent revascularization. In addition, vessels with abnormal non-hyperemic Pd/Pa, FFR, or both, all had equivalent TVF rates, and no differences in TVF rates were documented between the three patterns of abnormal pressure ratios.
      These data imply that combined application of non-hyperemic Pd/Pa and FFR efficiently identifies those lesions in which revascularization should undoubtedly be deferred, since vessels with combined non-hyperemic Pd/Pa and normal FFR were associated with excellent long-term clinical outcomes. On the other hand, these results also suggest that the decision to defer vessels from revascularization should potentially be based on combined use of hyperemic and non-hyperemic pressure ratios, since an increased event rate was observed in vessels with any abnormal pressure ratio, and there was no difference in long-term adverse event rates across the different patterns of abnormal pressure ratios. These findings are in line with a previous report that deferred vessels with discordant hyperemic and non-hyperemic pressure ratios portend a similarly increased risk for TVF [
      • Lee J.M.
      • Lee S.H.
      • Hwang D.
      • et al.
      Long-term clinical outcomes of nonhyperemic pressure ratios: resting full-cycle ratio, diastolic pressure ratio, and instantaneous wave-free ratio.
      ]. Further prospective studies are warranted to confirm these findings.

      4.3 Study limitations

      Some limitations of our study merit consideration. First, decision for revascularization for the stenosis of interest was driven by clinical practice guidelines at the time of the index procedure, but was ultimately at the discretion of the operator. Second, the vast majority of our study population consisted of patients with stable coronary artery disease. Hence, our findings cannot be directly extrapolated to the setting of non-culprit vessels in acute coronary syndromes. Third, there was no detailed information on the medication profiles of enrolled patients during the follow-up period, nor regarding angina burden. Moreover, it is important to recognize that the use of hyperemia-inducing agents is subjected to several limitations. We do not have data on alternatives for adenosine-derived FFR, such as the contrast medium induced FFR (cFFR) [
      • Kleczyński P.
      • Dziewierz A.
      • Rzeszutko Ł.
      • et al.
      Contrast medium Pd/pa ratio in comparison to fractional flow reserve, quantitative flow ratio and instantaneous wave-free ratio for evaluation of intermediate coronary lesions.
      ]. The combination of resting pd./pa and cFFR merits future research in order to facilitate a comprehensive physiological assessment in a more widespread popupulation. Finally, despite the large number of included vessels and the length of follow-up, this study suffers from the basic limitations of a retrospective registry, and these conclusions should therefore be confirmed in a randomized study.

      5. Conclusion

      Abnormal pressure ratios in both non-hyperemic and hyperemic conditions portend important prognostic value for TVF at 5-year follow up. Combined application of FFR and non-hyperemic Pd/Pa efficiently identifies those vessels with concordant normal resting and hyperemic pressure ratios of which long-term clinical outcomes are excellent. On the other hand, TVF rates were increased for vessels with any abnormal pressure ratio, both compared with concordant normal, as well as compared to vessels that underwent revascularization. These data lead to hypothesize that the decision to defer revascularization should potentially be based on combined non-hyperemic and hyperemic pressure ratios, but require confirmation in prospective studies.

      Author statement

      CB, GdW and TvdH were responsible for the conceptualization, formal analysis and interpretation of the data and drafting the first version of the manuscript. All other authors contributed significantly to the acquisition of the data, reviewing and finalizing the manuscript and approved the final version.

      Conflict of Interest

      Tvdh has received speaker fees and institutional research grants from Abbott and Philips. JML received research grants from Abbott and Philips. MEP has received speaker fees from Abbott and Philips. BKK has received institutional research grants from Abbott Vascular and Philips Volcano. JJP has received support as consultant for Philips/Volcano, and has received institutional research grants from Philips. The other authors report no relationship with industry related to this work.

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