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

Introduction The distal coronary-to-aortic pressure ratio (Pd/Pa) is a non-hyperaemic physiological index to assess the functional severity of coronary stenoses. Studies comparing Pd/Pa with fractional flow reserve (FFR) show superior diagnostic efficiency for myocardial ischaemia. Nevertheless, a direct comparison regarding long-term clinical outcomes is still not available. The present observational study compared the prognostic value of Pd/Pa and FFR for major adverse cardiac events (MACE) during a 10-year follow-up period after deferral of revascularisation. Methods Between April 1997 and September 2006, we evaluated 154 coronary stenoses (154 patients) in which revascularisation was deferred with intracoronary pressure and flow measurements during the resting and hyperaemic state. Long-term follow-up (median: 11.8 years) was performed to document the occurrence of MACE, defined as a composite of cardiac death, myocardial infarction and target vessel revascularisation. Results The study population comprised angiographically intermediate coronary stenoses, with a mean diameter stenosis of 53 ± 8%, and intermediate physiological severity with a median FFR of 0.82 (Q1, Q3: 0.76, 0.88). The association of Pd/Pa with long-term MACE was similar to that of FFR [FFR-standardised hazard ratio (sHR): 0.77, 95% confidence interval (CI): 0.61–0.98; Pd/Pa-sHR: 0.80, 95% CI: 0.67–0.96]. In the presence of disagreement between Pd/Pa and FFR, normal Pd/Pa was generally associated with high coronary flow reserve (CFR) and a favourable clinical outcome, whereas abnormal Pd/Pa was generally associated with CFR around the ischaemic cut-point and an impaired clinical outcome, regardless of the accompanying FFR value. Conclusion The present study suggests that Pd/Pa provides at least equivalent prognostic value compared with FFR. When Pd/Pa disagreed with FFR, the baseline index conferred superior prognostic value in this study population. Electronic supplementary material The online version of this article (10.1007/s12471-020-01365-6) contains supplementary material, which is available to authorized users.


Introduction
Guidelines on coronary revascularisation recommend the hyperaemia-dependent fractional flow reserve (FFR) for clinical decision-making, yet its clinical adoption has remained limited. As a corollary, the resting distal coronary-to-aortic pressure ratio (Pd/Pa) and the instantaneous wave-free ratio (iFR) were (re-)introduced with the aim of simplifying the use of coronary physiology in daily clinical practice by enabling its assessment during resting conditions [1][2][3]. Although baseline indices and FFR show equal diagnostic accuracy for positron emission tomographyderived flow abnormalities [4,5], studies using invasive Doppler-derived coronary flow reserve (CFR) as the reference standard documented superior identification of flow abnormalities by Pd/Pa and iFR over FFR [3,6,7]. Doppler-derived CFR is considered a critical determinant of myocardial ischaemia and has relevant prognostic value in the setting of stable ischaemic heart disease [8,9]. Accordingly, two landmark randomised clinical trials demonstrated that an iFR-guided revascularisation strategy is non-inferior to a FFR-guided revascularisation strategy in terms of clinical outcome at 1-year follow-up [10,11]. However, the long-term prognostic value of Pd/Pa has yet not been compared to that of FFR. Therefore, the aim of the present study was to compare the prognostic value of Pd/Pa, with that of FFR for major adverse cardiac events (MACE) during a 10-year follow-up period after deferral of revascularisation.

Data source
Between April 1997 and September 2006, we prospectively enrolled patients with angina referred for evaluation of ≥1 intermediate coronary stenosis (40%-70% diameter stenosis at visual assessment) in a series of study protocols [12][13][14] that included intracoronary pressure and flow measurements during resting and hyperaemic conditions. We excluded patients with ostial stenoses, serial stenoses, severe renal function impairment, significant left main stenosis, atrial fibrillation, myocardial infarction <6 weeks before screening, prior coronary artery bypass surgery (CABG), or visible collateral development to the perfusion territory of interest. The study protocols complied with the Declaration of Helsinki and were approved by the institutional ethics committee. All patients gave written informed consent.

Study procedures and subsequent treatment
Coronary angiography was performed according to standard practice. Quantitative coronary angiography analyses were performed offline using validated software (QCA-CMS version 3.32, MEDIS, Leiden, The Netherlands). Intracoronary nitroglycerin (0.1 µg) was given prior to invasive measurements. Intracoronary pressure and flow was measured with 0.014 pressure and Doppler sensor-equipped guide wires (Philips-Volcano, San Diego, CA, USA) during resting and hyperaemic conditions. Hyperaemia was induced by an intracoronary bolus of adenosine (20-40 µg). Revascularisation was performed at the operator's discretion, and decisions on further treatment and medication during follow-up were entirely left to the discretion of the treating cardiologist [8,15].

Long-term follow-up
Three-, 6-, 12-month and long-term follow-up was performed by clinical visit or telephone contact to document the occurrence of MACE, defined as the composite of cardiac death, acute myocardial infarction attributable to the target vessel, and clinically driven revascularisation of the target-vessel by CABG or percutaneous coronary intervention (PCI). All patient-reported events were verified and adjudicated after evaluating hospital records or contacting the treating physicians.

Statistical analysis
In the presence of multiple stenoses of intermediate severity, one was randomly marked the index stenosis and used for subsequent analyses. Normality of the distribution and homogeneity of variances were tested with the Shapiro-Wilk statistic and Levene's test, respectively. Continuous variables are presented as mean ± standard deviation or median [1st, 3rd quartile (Q1, Q3)], and compared with Student t-test or Mann-Whitney U-test. Categorical variables are presented as frequency (percentage) and compared with Fisher exact test. The prognostic value of FFR and Pd/Pa for 10-year MACE was assessed using Cox regression analyses, adjusted for the effect of relevant clinical characteristics. The best-fit model for adjustment was identified using Akaike's information Resting distal-to-aortic pressure ratio (Pd/Pa) is defined as the distal coronary pressure to aortic pressure ratio during baseline conditions. Fractional flow reserve is defined as the distal coronary pressure to aortic pressure ratio during hyper-aemic conditions induced by hyperaemic agents. Coronary flow reserve is defined as the coronary flow velocity during hyperaemia to coronary flow velocity during baseline ratio measured distal from the stenosis of interest

Patient population
A total of 228 patients (299 stenoses) were included. Revascularisation was deferred in 159 patients, in 154 of whom (183 stenoses) resting and hyperaemic coronary pressure and flow velocity data and long-term

Discussion
The current article is the first to document that Pd/Pa demonstrates a continuous and independent relationship with subsequent long-term clinical outcomes which is at least equivalent to that of FFR, and that Pd/Pa exceeds FFR as a risk stratification tool at the contemporary clinical cut-off values. When discordance with FFR occurs, Pd/Pa may therefore confer superior clinical value.

Prognostic relevance of resting versus hyperaemic stenosis pressure drops
The superior prognostic relevance of resting Pd/Pa over FFR at contemporary cut-offs may be explained by a better agreement of Pd/Pa with coronary flow. Our observations support those of previous studies that demonstrated a better relationship between resting indices and Doppler-derived CFR than for FFR and Doppler-derived CFR [3,6,7]. It has been documented that, when FFR disagrees with CFR, CFR has superior prognostic value over FFR for long-term  Values are number (%), mean ± standard deviaion, median (1st, 3rd quartile) FFR fractional flow reserve; Pd/Pa resting distal coronary-to-aortic pressure ratio; PCI percutaneous coronary intervention; ACE angiotensin converting enzyme; APV average peak flow velocity; CFR coronary flow reserve clinical outcomes [8,9,15]. This is likely due to the fact that FFR and CFR move in opposite directions from resting conditions to hyperaemia: FFR decreases and becomes more abnormal, while CFR increases and becomes more normal. Hence, the combination of an abnormal FFR and normal Pd/Pa may occur on the basis of a normal Pd/Pa value that decreases to abnormal FFR values at hyperaemia due to a large increase in coronary flow with a normal CFR. Such stenoses are considered non-flow-limiting, and likely have excellent clinical outcomes when managed medically [8,9,15,17,18]. On the other hand, an abnormal Pd/Pa may occur in combination with a normal FFR when a stenosis may coexist with an exhausted CFR as a result of compensatory vasodilation during resting conditions to maintain resting perfusion. The abnormal Pd/Pa may only decrease to normal FFR values due to the limited increase in coronary flow from baseline to hyperaemia. The optimal management of vessels exhibiting this haemodynamic pattern remains a matter of debate [19]. Since myocardial function thrives on coronary flow and not on perfusion pressure, reductions in distal coronary perfusion, however, should not be associated with impaired myocardial function as long as adequate coronary flow is present [20]. This is supported by a recent randomised study documenting excellent clinical outcomes when magnetic resonance imaging-defined perfusion deficits were used to guide coronary intervention [18]. Since myocardial function and clinical outcomes are determined by coronary flow independent of coronary pressure [8,9,15,20], and Pd/Pa has better agreement with invasively measured coronary flow than FFR [3], this may provide an explanation why Pd/Pa has superior prognostic value when there is disagreement with FFR.

Comparison with previous FFR studies
Importantly, our observation that there was no difference in clinical outcomes between FFR-positive and FFR-negative cases might wrongly be interpreted to be in contrast with the findings from FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) and FAME II [16,21]. FAME compared FFR versus angiography for guidance of revascularisation and documented superior clinical outcome using a FFR-guided revascularisation strategy. FAME II compared PCI + optimal medical therapy (OMT) versus OMT for treatment of FFR-positive lesions and documented superior clinical outcome for lesions treated with PCI + OMT. It is important to note that the average FFR in FFR-positive stenosis in FAME was 0.60 ± 0.14 [21]. In FAME II, the average FFR in FFRpositive stenoses amounted to 0.68 ± 0.10 in the medical therapy group and 0.68 ± 0.15 in the PCI group [16]. Hence, the stenoses included in the FAME studies were physiologically much more severe than those encountered typically in contemporary daily practice. Most importantly, among these severe stenoses in the FAME II study, around 60% of lesions in the medical therapy group did not require any coronary intervention within 2 years after initial deferral from revascularisation-a result that is consistent up to 5-year follow-up. The present study involves true physiologically intermediate stenoses as typically encountered in daily practice (Tab. 1; [2,10,11,18]). This is relevant for the observed differences in clinical outcomes compared with the FAME studies: FFR reflects a risk continuum, where risk for adverse events becomes higher with decreasing FFR [22]. This risk continuum for FFR was also noted in the Cox regression analysis for FFR in the present study. However, the FAME II trial showed that the benefit of revascularisation was supreme in vessels with FFR < 0.65. Similarly, a recent patient-level meta-analysis on the prognostic value of FFR identified an optimal 0.67 FFR threshold for clinical outcomes [22]. These findings support the lack of a difference in MACE between FFR ≤ 0.80 and > 0.80 in the present study, where, similar to daily clinical practice, most FFR values in FFR-positive stenoses were >0.70 and therefore above the FFR thresholds associated with impaired clinical outcomes.

Limitations
The relatively small sample size limits the statistical power and the strength of the conclusions, especially for the discordant groups. We used intracoronary administration of 20-40 µg of adenosine, which remains a subject for debate. However, it has been documented that the observed FFR is already within 0.02 of its minimal value at intracoronary adenosine dosages above 23 µg [23]. Since the test/retest repeatability of FFR itself has a standard deviation of 0.02 [24], FFR differences < 0.02 are smaller than the variability of the FFR measurement itself and, therefore, are considered clinically irrelevant [23]. It is therefore unlikely that the dose of adenosine has interfered with the results in the present study. This is supported by the limited differences in FFR values derived from lowdose intracoronary versus intravenous adenosine administration [25], and by the fact that such small differences in FFR between intravenous and intracoronary adenosine were documented to be clinically irrelevant in the DEFER trial [26]. Additionally, this study is limited by the assessment of adverse events at long-term follow-up partly performed by telephone contact. Such an approach is sensitive towards patient recall bias, which may result in under-reporting of adverse events. Nonetheless, the long-term MACE rates reported in the present study are comparable with those reported in contemporary studies using FFR guidance [26,27].

Conclusion
The present study documents that Pd/Pa demonstrates a continuous and independent relationship with subsequent long-term clinical outcomes which is at least equivalent to that of FFR, and suggests that Pd/Pa exceeds FFR as a risk stratification tool at its contemporary cut-off value.
M. Voskuil, R.J. de Winter and J.G.P. Tijssen declare that they have no competing interests.
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