FormalPara What’s new?

  • The distal coronary-to-aortic pressure ratio (Pd/Pa) demonstrates a continuous and independent relationship with subsequent long-term clinical outcomes.

  • The prognostic value of Pd/Pa is at least equivalent to that of fractional flow reserve (FFR), but exceeds FFR as a risk stratification tool at their contemporary clinical cut-off values.

  • When Pd/Pa disagreed with FFR, Pd/Pa conferred superior prognostic value in this study population.

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 tomography-derived 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.

Methods

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.

Haemodynamic data analysis

The physiological indices were defined as:

  • FFR = mean Pd/mean Pa (hyperaemia)

  • Pd/Pa = mean Pd/mean Pa (resting conditions)

  • CFR = hyperaemic average peak flow velocity (APV)/baseline APV

For dichotomous evaluations, FFR ≤ 0.80 [16], and Pd/Pa ≤ 0.92 [2] were considered abnormal (Fig. 1).

Fig. 1
figure 1

Example of intracoronary pressure and flow measurements. 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 hyperaemic 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

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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 criterion, where candidate covariates were: clinical characteristics (Tab. 1) and the interrogated vessel. All Cox proportional-hazards models were preceded by verification of the proportional hazard assumption using Schoenfeld’s residuals. Results are presented as standardised hazard ratios (sHRs) and their 95% confidence intervals (CIs), estimated from the Cox proportional-hazard models by exponentiating the β‑coefficient multiplied by the SD[exp(β × SD)]. Next, according to their clinical cut-off values, 10-year MACE rates for normal and abnormal FFR and Pd/Pa were estimated using the Kaplan-Meier (KM) method, and differences were tested with the Wilcoxon-Breslow-Gehan test of equality (Breslow p). Finally, KM estimates of 10-year MACE were evaluated across the four quadrants of Pd/Pa and FFR (dis)agreement, where differences were evaluated with Breslow p. A p-value below the 2‑sided α‑level of 0.05 was considered statistically significant. The STATA 13.1 statistical software package (StataCorp, College Station, TX, USA) was used for all calculations.

Table 1 Demographic, angiographic and physiological characteristics
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Results

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 follow-up were available. In patients with multiple stenoses, one was chosen at random for MACE analyses, which consequently included 154-patients with 154 stenoses. Median follow-up in these patients was 11.8 years (Q1, Q3: 10.0, 13.3 years). Mean age was 60 ± 11 years and 71% of patients were male. Additional baseline characteristics are depicted in Tab. 1.

Angiographic and physiological measurements

The study population comprised angiographically intermediate 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) (Fig. 2), median Pd/Pa of 0.94 (Q1, Q3: 0.91, 0.97) and median CFR of 2.5 (Q1, Q3: 2.1, 2.9). Stenoses were haemodynamically significant in 43.5% and 34.4% of cases according to FFR and Pd/Pa, respectively. Angiographic and physiological characteristics are depicted in Tab. 1.

Fig. 2
figure 2

Distribution of fractional flow reserve values across the study population

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Clinical outcome after deferral of revascularisation stratified by FFR and Pd/Pa

The best-fit model for adjustment included angiotensin-converting-enzyme inhibitor use, the presence of diabetes mellitus and age. Cox regression analysis adjusted for these variables demonstrated that FFR and Pd/Pa were both significantly and equivalently associated with long-term MACE [FFR-sHR: 0.77 (95% CI: 0.61–0.98), p = 0.033; Pd/Pa-sHR: 0.80 (95% CI: 0.67–0.96), p = 0.014] (Tab. 2). Fig. 3 shows the KM curves for cumulative MACE up to 10 years of follow-up according to normal or abnormal results for FFR and Pd/Pa. At 10-year follow-up, the KM estimate of MACE was not significantly different for stenoses with abnormal versus normal FFR (FFR ≤ 0.80: 45.8% vs FFR > 0.80: 34.4%; Breslow p = 0.17: Fig. 3a). In contrast, the KM estimate of MACE at 10-year follow-up for stenoses with abnormal Pd/Pa was significantly higher than for stenoses with normal Pd/Pa (Pd/Pa ≤ 0.92: 52.0% vs Pd/Pa > 0.92 32.7%; Breslow p = 0.006: Fig. 3b).

Table 2 Univariate and adjusted Cox regression analyses for long-term major adverse cardiac events
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Fig. 3
figure 3

Kaplan-Meier estimates of major adverse cardiac event (MACE) rate during 10 years of follow-up, stratified by: a fractional flow reserve (FFR); FFR ≤ 0.80 was considered abnormal. b Resting distal coronary-to-aortic pressure ratio (Pd/Pa). Pd/Pa ≤ 0.92 was considered abnormal

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Clinical outcome according to discordance between FFR and Pd/Pa

Pd/Pa agreed with FFR in 71% of stenoses (110 out of 154), of which 25% of the stenoses (38 out of 154) were concordant abnormal, and 47% of stenoses (72 out of 154) were concordant normal. Pd/Pa disagreed with FFR in 29% of stenoses (44 out of 154), and was characterised by abnormal FFR and normal Pd/Pa in 19% of stenoses (29 out of 154) and by normal FFR and abnormal Pd/Pa in 10% of stenoses (15 out of 154) (Fig. 4a). Fig. 4b depicts the KM curves for cumulative MACE up to 10-year follow-up stratified by Pd/Pa and FFR agreement. A normal Pd/Pa was generally associated with a favourable clinical outcome, regardless of the accompanying FFR value, whereas abnormal Pd/Pa was generally associated with an impaired clinical outcome, regardless of the accompanying FFR value (overall Breslow p = 0.04).

Fig. 4
figure 4

a, b Discordance between resting distal coronary to aortic pressure ratio (Pd/Pa) and fractional flow reserve (FFR). a Scatterplot of Pd/Pa and FFR. The dotted lines represent the respective cut-off values for Pd/Pa (0.92), and FFR (0.80). b Kaplan-Meier estimates of major adverse cardiac event (MACE) rate during 10 years of follow-up, stratified by Pd/Pa-FFR discordance

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Agreement with CFR

CFR was significantly different across the four quadrants of Pd/Pa and FFR (dis)agreement (Tab. 3). A normal Pd/Pa was generally associated with high CFR and an abnormal Pd/Pa was generally associated with CFR values around the ischaemic cut-off, regardless of the accompanying FFR value (overall p = 0.006).

Table 3 Study population characteristics according to FFR—Pd/Pa disagreement
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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 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 FFR-positive 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 low-dose 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.