Summary
Physiology-guided revascularization plays a pivotal role in the management of coronary artery disease (CAD). In recent years, non-hyperemic indices such as diastolic pressure ratio (dPR) and resting full-cycle ratio (RFR) have gained prominence in clinical practice. However, data on the long-term outcomes of deferred revascularization guided by these indices remain limited. In this study, we evaluated the 1-year outcomes among 204 patients with CAD involving 408 lesions, where revascularization was deferred based on dPR or RFR assessments. The incidence of major adverse cardiovascular events, defined as a composite of all-cause mortality, myocardial infarction, and target vessel revascularization, along with individual event rates, was low. These outcomes were comparable to those reported in the literature for fractional flow reserve-guided strategies.
Introduction
The incidence of coronary artery disease (CAD) is projected to increase primarily due to the aging population [1]. Despite advancements in optimal medical therapy (OMT), careful patient selection for revascularization remains a critical component of CAD management [2]. According to the most recent European Society of Cardiology (ESC) guidelines for CAD, functional assessment to identify ischemia-causing lesions holds a Class IA recommendation [3]. However, these guidelines are largely based on randomized controlled trials (RCTs) evaluating hyperemic measurements using fractional flow reserve (FFR). Furthermore, the RCTs had several exclusion criteria [4–6]. In real-world clinical practice, many patients who would typically be excluded from such trials are assessed in catheterization laboratories using guideline-recommended methods. Moreover, the reliability of functional evaluation remains a topic of debate in various clinical settings, including left ventricular hypertrophy (LVH), aortic stenosis (AS), diabetes, sex differences, and complex CAD anatomy [7, 8]. The rapid development of alternative wire-based methods other than FFR, such as resting full-cycle ratio (RFR) and diastolic pressure ratio (dPR), has led to their frequent use in daily clinical settings. Data on their clinical utility and long-term outcomes are limited.
Aim
We aimed to evaluate the outcomes of deferred revascularization among all patients undergoing non-hyperemic functional assessments in different settings.
Material and methods
Study population
The study utilized data from a single center, encompassing all patients who underwent physiological assessments in the catheterization laboratory at Wroclaw University Hospital from January 2022 to June 2022. The inclusion criteria were as follows: (1) adult patients with indications for coronary angiography for whom the interventional cardiologist elected to perform wire-guided functional measurements, (2) assessments performed with all types of physiological evaluations, including FFR, dPR, and RFR. The exclusion criterion was active malignancy. Participants meeting all inclusion criteria and not meeting the exclusion criterion were deemed eligible for this study. Intermediate lesions assessed through physiological evaluation were defined as those exhibiting a narrowing within the range of 50–80% in visual assessment. Based on physiological results, patients were referred for revascularization through percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) if RFR and dPR values were < 0.89 or FFR was < 0.80, or they were directed to OMT if RFR and dPR values were > 0.89 or FFR was > 0.80. If necessary, treatment decisions were made by the Heart Team. All functional measurements were performed using commercially available wires. Patients assigned to PCI underwent stenting of all measured lesions using drug-eluting stents, while those directed to OMT were managed by the current ESC guidelines at the time of the procedure. In patients presenting with myocardial infarction (MI), functional assessment was only measured in non-culprit lesions. Baseline characteristics, including demographics, laboratory data, comorbidities, indications for coronary angiography, and details of physiological assessments, were extracted from electronic medical records. The study protocol received approval from the ethics committee at Wroclaw Medical University.
Outcomes
The primary endpoint for long-term follow-up was the occurrence of major adverse cardiovascular events (MACE), comprising all-cause death, MI, and target vessel revascularization (TVR). MI was defined according to the prevailing ESC guideline criteria [8, 9]. TVR was specified as subsequent revascularization of the vessel evaluated by the functional tool, either through PCI or CABG. Clinical follow-up was conducted either during subsequent rehospitalizations at the same center or via telephone contact over the following year.
Statistical analysis
The data were summarized using median with interquartile range (IQR), frequency (percentage), or mean with standard deviation, depending on whether the variables were parametric or nonparametric. Pearson’s χ2 test for independence or Fisher’s exact test was applied to categorical variables. Statistical significance was considered at a p-value < 0.05. Missing values for other parameters were not imputed. Statistical analyses were performed using Statistica version 13.3.
Results
321 consecutive patients undergoing functional coronary evaluations were screened for eligibility. Sixteen patients were excluded due to active malignancy at the initial stage. During the 1-year observation period, 15 patients were lost to follow-up. Finally, 290 patients were included in the analysis.
The cohort had a mean age of 68.2 ±8.9 years, and 76.8% were male. Hypertension was present in 63.1% of the population, diabetes mellitus in 32.6%, LVH in 49.3%, and chronic kidney disease (CKD) at any stage in 53.4%. A history of any type of heart failure (HF) was observed in 26.2% of patients, prior MI in 24.1%, previous PCI in 38.3%, and prior CABG in 3.1%. The median hemoglobin level was 13.8 g/dl (IQR: 12.8–14.8), median troponin level 101.0 ng/l (IQR: 70.3–192.4), median NT-proBNP concentration 303.0 pg/ml (IQR: 112.5–1013.2), median LDL cholesterol level 87.0 mg/dl (IQR: 70.0–113.0), and median HbA1c 5.9% (IQR: 5.5–6.4).
The primary indications for coronary angiography were chronic coronary syndrome (CCS) in 57.2%, HF in 9.3%, unstable angina (UA) in 13.8%, non-ST elevation myocardial infarction (NSTEMI) in 4.5%, second-stage revascularization following ST-elevation myocardial infarction (STEMI) in 1.7%, evaluation for surgery due to aortic stenosis in 8.3%, evaluation for mitral regurgitation surgery in 0.6%, arrhythmia in 2.4%, and routine coronary angiography post-heart transplantation in 2.0%. Detailed baseline characteristics of the study population are presented in Table I.
Table I
Baseline characteristics (n = 290)
[i] CAG – coronary angiography, NSTEMI – non-ST elevation myocardial infarction, STEMI – ST elevation myocardial infarction, LVH – left ventricular hypertrophy, MI – myocardial infarction, PCI – percutaneous coronary intervention, CABG – coronary artery bypass grafting, COPD – chronic obstructive pulmonary disease, TIA – transient ischemic attack, LVEF – left ventricular ejection fraction, NT-proBNP – N-terminal prohormone of brain natriuretic peptide, TSH – thyroid stimulating hormone, CRP – C-reactive protein, LDL – low-density lipoprotein, HbA1c – hemoglobin A1c, ACEI/ARB – angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, ARNI – angiotensin receptor-neprilysin inhibitor, NOAC – non-vitamin K antagonist oral anticoagulant.
A total of 536 coronary lesions were assessed, including 230 evaluated using dPR, 243 using RFR, and 63 using FFR. In 23 (36.5%) cases, FFR was used as the gold standard to confirm borderline dPR or RFR values. Positive findings were noted in 17.4% of dPR assessments, 13.2% of RFR evaluations, and 25.4% of FFR measurements. There was no statistically significant difference in revascularization eligibility between dPR and RFR (p = 0.20) or dPR and FFR (p = 0.15), whereas FFR more frequently led to revascularization compared to RFR (p = 0.01). Overall, 204 (70.3%) patients were deemed ineligible for revascularization based on the non-hyperemic measurements. Further details regarding functional evaluation outcomes are provided in Table II.
Table II
Procedural results
[i] dPR – diastolic pressure ratio, RFR – resting full-cycle ratio, FFR – fractional flow reserve, LM – left main coronary artery, LAD – left anterior descending coronary artery, Cx – circumflex coronary artery, OM – obtuse marginal branch, Dg – diagonal branch, RCA – right coronary artery, PDA – posterior descending artery, PL – posterolateral branch.
At the 1-year follow-up, in the cohort with deferred revascularization, MACE occurred in 7.8%, all-cause mortality in 4.9%, MI in 0.5%, and unplanned revascularization in 2.5%. Among patients who underwent revascularization (PCI or CABG), MACE occurred in 10.5%, all-cause mortality in 4.7%, MI in 1.2%, and unplanned revascularization in 4.7%. No statistically significant differences were observed between the deferred and revascularized groups for any endpoints: MACE (p = 0.47), all-cause mortality (p = 0.92), MI (p = 0.55), and unplanned revascularization (p = 0.35). Detailed outcomes are presented in Tables III and IV.
Table III
Outcomes among patients with deferred revascularization
Table IV
Outcomes among patients with performed revascularization. Outcomes among patients with deferred revascularization
Discussion
The main findings of this study are: (1) deferred revascularization guided by dPR and RFR pressure measurements is demonstrated to be safe and comparable, (2) the use of non-hyperemic pressure assessment tools in clinically ambiguous scenarios is demonstrated to be a reliable and effective approach, (3) FFR remains the gold standard for evaluating inconclusive findings obtained from non-hyperemic pressure assessments.
Over the past two decades, multiple studies have consistently demonstrated the safety of deferring revascularization based on FFR guidance [5]. The pivotal FAME 2 trial established the safety of FFR-guided deferment for revascularization in cases with an FFR value exceeding 0.80. At 1-year follow-up, this approach was associated with rates of 0.3% for cardiac death, 3.2% for MI, and 11.1% for urgent revascularization. However, the trial excluded patients with left main coronary artery disease, recent MI, prior CABG, and reduced left ventricular ejection fraction. Similarly, the DEFER trial evaluated patients with FFR > 0.75, deferring revascularization and reporting outcomes over a 5-year follow-up [10]. The rates of cardiac death, MI, and TVR were 3.3%, 0%, and 8.8%, respectively. Notably, this study excluded patients presenting with unstable angina. In one of the largest observational studies, the IRIS-FFR registry analyzed outcomes for 6,468 lesions in 5,847 patients where revascularization was deferred based on FFR. At 1-year follow-up, the incidence of MACE per lesion-year ranged from 0% to 7.93% for lesions with an FFR > 0.75. This registry excluded patients with overt heart failure, graft vessels, and lesions with a thrombolysis in myocardial infarction flow < 3 [11]. The J-CONFIRM registry included 1,262 patients and analyzed outcomes for 1,447 lesions where revascularization was deferred with an FFR > 0.80 [12]. Over 2 years, the rates of cardiac death, MI, and TVR were 0.41%, 0.41%, and 5.2%, respectively. This study excluded patients with prior MI, chronic total occlusions, and graft lesions. A subgroup analysis within this cohort demonstrated that elderly patients (aged ≥ 75 years) did not experience an increased risk of adverse events due to the deferred revascularization over a 5-year follow-up period [13]. In our study, the incidence of adverse events in the group with deferred revascularization remained consistently low, demonstrating outcomes comparable to those observed in previous investigations using FFR measurements.
The increasing application of non-hyperemic methods in coronary assessment stems from multiple factors. Non-hyperemic indices offer several advantages, including the elimination of the need for hyperemia induction, leading to shorter procedure times, avoidance of adverse effects associated with adenosine administration, and enabling the evaluation of serial lesions. Notably, the non-inferiority of instantaneous wave-free ratio (iFR) compared to FFR for MACE has been demonstrated in two large RCTs [14, 15]. Current clinical guidelines recommend the use of dPR and RFR as alternative diagnostic tools in Class IIb [3]. However, data on these indices remain more limited, with some studies highlighting potential discrepancies between these tools [16, 17]. Omori et al. demonstrated that dPR and RFR exhibit similar diagnostic accuracy to iFR measurements, though their study excluded patients with CABG, in-stent restenosis, and left main trunk disease [18]. Similarly, Svanerud et al. reported diagnostic equivalence between RFR and iFR, but their study excluded patients with CABG, severely calcified lesions, or a history of MI within 5 days before assessment [19]. In our study, we observed comparable revascularization eligibility outcomes between dPR and RFR measurements (17.4% vs. 13.2%, p = 0.20) and no difference between dPR and FFR eligibility results (p = 0.15), but FFR in comparison with RFR more often yielded positive results (p = 0.01). Discrepancies between FFR and RFR outcomes should be interpreted with the causes. These results can be attributed to the laboratory’s approach, wherein FFR is employed to ascertain the hemodynamic significance of lesions when non-hyperemic assessments produce borderline results, as occurred in 36.5% of cases. Two studies conducted by Casanova-Sandoval and Malmberg et al. proposed a hybrid approach utilizing RFR and FFR as needed [20, 21]. The use of non-hyperemic indices as a primary tool technique may lead to lower use of hyperemic agents, simplify coronary procedures, and in consequence lead to greater adoption of physiology-guided revascularization. One proposed theory suggests that LVH may influence FFR measurements through two mechanisms. First, LVH can elevate FFR values due to extravascular compression and increased intraventricular pressures. Conversely, hypertrophied myocardial tissue is characterized by a higher capillary density, potentially increasing hyperemic flow. However, Chhatriwalla et al. demonstrated that an elevated left ventricular mass index does not significantly affect FFR measurements. Additionally, findings from a substudy of the DANAMI-3-PRIMULTI trial indicated no difference in clinical outcomes between patients with and without LVH following FFR-guided revascularization [22]. Consistent with these findings, in our study, despite a 49.3% prevalence of LVH, clinical outcomes remained favorable. In contrast, several studies have reported worse clinical outcomes in diabetic patients who underwent FFR-guided deferred revascularization [23, 24]. This population is often characterized by endothelial dysfunction and impaired microvascular function, which may theoretically impact FFR measurements. However, other studies suggest that these factors do not significantly alter FFR values [25, 26]. The observed worse outcomes in diabetic patients may instead be attributed to accelerated atherosclerosis driven by hyperglycemia, leading to lesions initially deemed insignificant by FFR becoming hemodynamically significant more rapidly. A similar effect should be considered in patients with chronic kidney disease (CKD) [27].
The primary concerns regarding the use of FFR in patients with severe aortic stenosis (AS) stem from the potential impact of left ventricular remodeling secondary to AS, which may attenuate maximal hyperemia. Furthermore, the coexistence of AS and coronary artery stenosis represents a tandem lesion, potentially complicating FFR measurements. Pesarini et al. stated that FFR assessments are generally consistent before and after transcatheter aortic valve implantation (TAVI). However, borderline FFR values may decrease after TAVI, leading to changes in PCI eligibility in approximately 15% of cases [28]. Data on non-hyperemic indices in the context of AS primarily focus on iFR. Studies have indicated that iFR measurements may exhibit greater variability after TAVI compared to FFR [29]. Moreover, the conventional iFR threshold of 0.89 for clinical decision-making has been shown to have lower diagnostic accuracy than the established FFR threshold of 0.80 [30]. Evidence regarding the use of RFR and dPR in AS is limited. A small study by Sabbah et al. suggested that pre-TAVI FFR assessment results in a lower reclassification rate at 6 months compared to RFR [31]. While current guidelines permit the use of non-hyperemic indices to evaluate the hemodynamic significance of epicardial coronary artery stenosis, there is insufficient evidence supporting the safety of dPR and RFR in the context of AS. FFR remains the gold standard for this purpose [32]. Our study evaluated 24 patients with AS (8.3%) using non-hyperemic indices, and 1 case of all-cause mortality occurred during the 6-month follow-up period, but the sample size is too small to draw definitive conclusions. Further investigation is warranted to assess the safety and clinical utility of dPR and RFR in patients with AS.
This study has several limitations. First, follow-up data were unavailable for 15 patients. Second, the relatively low number of observed events during the follow-up period precluded the use of logistic regression analysis to identify independent predictors of clinical endpoints.
Conclusions
In this small observational study, the clinical outcomes among patients with deferred revascularization based on dPR and RFR measurements were low and comparable to those observed with FFR-guided decisions in the literature. Notably, these findings remained consistent across specific subgroups. However, dedicated, large randomized trials are necessary to comprehensively evaluate the safety and efficacy of these non-hyperemic assessment methods.
