Author + information
- Received March 21, 2018
- Revision received July 19, 2018
- Accepted July 24, 2018
- Published online October 15, 2018.
- Futoshi Yamanaka, MDa,∗ (, )
- Koki Shishido, MDa,
- Tomoki Ochiai, MDa,
- Noriaki Moriyama, MDa,
- Kazumasa Yamazaki, MDb,
- Ayumu Sugitanic,
- Tomoyuki Tani, MDb,
- Kazuki Tobita, MDa,
- Shingo Mizuno, MDa,
- Yutaka Tanaka, MD, PhDa,
- Masato Murakami, MD, PhDa,
- Saeko Takahashi, MDa,
- Seiji Yamazaki, MDb and
- Shigeru Saito, MDa,b
- aDepartment of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
- bDepartment of Cardiology, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
- cDepartment of Biometrics, Institute of Biomedical Research, Sapporohigashi Tokushukai Hospital, Sapporo, Japan
- ↵∗Address for correspondence:
Dr. Futoshi Yamanaka, Department of Cardiology, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, Japan.
Objectives This study investigated the diagnostic performance of instantaneous wave-free ratio (iFR) in patients with aortic valve stenosis (AS).
Background The iFR was introduced as a new, nonpharmacologic stress index of coronary stenosis severity. However, the diagnostic performance of iFR has not been sufficiently explored in patients with severe AS.
Methods We analyzed 95 consecutive patients with AS (57 women) demonstrating intermediate coronary artery stenosis (116 vessels), and compared the iFR values with fractional flow reserve (FFR) values and with adenosine-stress myocardial perfusion imaging as indicators of myocardial ischemia.
Results The median value and interquartile range (first quartile [Q1], third quartile [Q3]) of the iFR was 0.86 (Q1 to Q3 range, 0.76 to 0.93), and that of the FFR was 0.84 (Q1 to Q3 range, 0.76 to 0.91). The iFR values correlated well with the FFR values (R = 0.854; p < 0.0001). A receiver operating characteristic analysis demonstrated an optimal cutoff of 0.82 for the iFR to indicate an FFR ≤0.75, with an area under the curve of 0.92. The optimal iFR cutoff value indicating myocardial ischemia on perfusion scintigraphy was 0.82 (area under the curve: 0.84).
Conclusions In patients with severe AS, a good correlation exists between iFR and FFR. Both the iFR and FFR values exhibit good correlation with perfusion scintigraphy–identified myocardial ischemia. The iFR could be a safe diagnostic tool for patients with severe AS. (The Impact of FFR and iFR in Patients with Severe Aortic Stenosis; UMIN000024479)
Coronary artery disease is frequently seen in patients with aortic valve stenosis (AS) (1), and the current guidelines recommend objectively and definitively assessing these patients for the presence of myocardial ischemia (2–4). However, the optimal method for evaluating myocardial ischemia in patients with AS has not yet been established. In addition, despite the increased focus on coronary artery disease in this patient population, its optimal management remains unclear.
Fractional flow reserve (FFR) represents the standard indicator used in the catheterization laboratory to assess the severity of functional stenosis (2–4). Based on clinical evidence, the current guidelines strongly recommend evaluating patients with intermediate coronary artery stenosis for myocardial ischemia (2–4). FFR measurements require that myocardial resistance be minimal and constant, which can be simply achieved in daily practice with intravenous adenosine infusion. Although most patients feel chest discomfort and breathlessness during adenosine infusion, these symptoms are generally well-tolerated (5). However, the safety of adenosine infusion in patients with severe AS is controversial.
The instantaneous wave-free ratio (iFR) was introduced as an alternative method for assessing pressure differences across stenosed lesions during the wave-free period of the cardiac cycle (6). This index is measured at rest and does not require adenosine administration. A trial examining iFR- and FFR-guided percutaneous coronary intervention demonstrated the noninferiority of the iFR method with respect to 1-year rates of major adverse cardiovascular events (7,8).
Despite these encouraging reports, the usefulness of iFR has not been sufficiently established in patients with AS. Although several reports have been published regarding the use of iFR in patients with AS, none has reported a comparison with myocardial perfusion imaging as the reference standard. Additionally, coronary microvascular resistance has been reported to be potentially higher in patients with AS than in those without AS (9). This high coronary microvascular resistance might affect the optimal iFR cutoff value used to indicate myocardial ischemia in these patients (10). Therefore, the present study compared the diagnostic performances of iFR and FFR with myocardial perfusion images, as indicators of myocardial ischemia.
Patient population and study design
This exploratory research was conducted as a prospective 2-center research designed to investigate the diagnostic performance of iFR in patients with intermediate coronary artery stenosis and severe AS. The registry consecutively enrolled all patients who underwent iFR and FFR measurement for the functional assessment of coronary artery stenosis.
Severe AS was defined as an aortic-valve area of ≤1.0 cm2, a mean aortic-valve gradient of 40 mm Hg or more, or a peak aortic-jet velocity of 4.0 m/s or more. All patients had New York Heart Association functional class II, III, or IV symptoms. The exclusion criteria were an adenosine contraindication (e.g., active stage of bronchial asthma), left main- (stenosis ≥50% of the diameter of the affected vessel) or triple-vessel disease, previous myocardial infarction in the same coronary artery, tandem lesions (separated by >10 mm) requiring independent evaluation in the same coronary artery, or failure to provide written informed consent.
This research was approved by the institutional review board at both participating sites and was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000024479). All data were prospectively collected at each center, and all participants provided written informed consent.
The primary end point was to assess the optimal cutoff value of iFR for indicating myocardial ischemia. The secondary end points were to assess the reproducibility of the iFR, the correlation between iFR and FFR, and the safety of adenosine infusion in patients with AS.
Coronary angiography, right heart catheterization, and FFR measurement protocol
Conventional coronary angiography was performed in all patients using standard catheters (larger than 5F). Intermediate coronary artery stenosis was defined as 30% to 70% stenosis (visual estimation) in 1 or 2 major epicardial coronary arteries. All coronary angiography procedures and pressure studies were performed by highly experienced interventional cardiologists. At least 2 orthogonal views of the lesion were obtained, and the frame that indicated more severe stenosis at end-diastole was used for the quantitative coronary angiography measurements. The minimal luminal diameter, reference diameter, lesion length, and percent diameter stenosis were measured after calibrating pixel size using a contrast-filled diagnostic catheter. A 7F Swan-Ganz catheter was used for obtaining pressure values in the right heart, including the right atrial, right ventricular, pulmonary arterial, and pulmonary capillary wedge pressures.
The iFR and FFR measurements were obtained using a coronary pressure guidewire (Philips Volcano, San Diego, California). After the pressure wire was positioned at the distal segment of the target lesion, the iFR was measured twice (at least 30-s apart during stabilized heart rate), followed by 1 FFR measurement. For FFR measurements, hyperemia was induced by intravenous adenosine administration (140 μg/kg/min) via a central or large antecubital vein (11,12). The FFR was calculated as the mean ratio between the distal coronary pressure and the proximal aortic pressure during stable hyperemia.
Pharmacological stress single-photon emission computed tomography was performed. Adenosine (0.72 mg/kg) was infused over 6 min (13,14); 3 min before the end of the adenosine infusion, 99mTc (370 MBq) was injected intravenously. 99mTc scintigraphic scanning was performed 30 min after the end of the adenosine infusion, and delayed rest images were obtained 3 h later. A digital gamma camera (eSOFT Siemens Healthineers, Erlangen, Germany) was rotated over a 180° arc. Scintigraphic images were assessed using a 17-segment model; care was taken to select the segments that corresponded to the coronary territories. Scintigraphy findings were analyzed in tandem by a highly experienced radiologist and cardiologist; intraobserver and interobserver analyses were performed.
All statistical analyses were performed using JMP 13.1 (SAS Institute, Cary, North Carolina) and R software version 3.3.1 (R Foundation for Statistical Computing, Vienna, Austria). Continuous variables are expressed as mean ± SD or as median (interquartile range), depending on their distribution. Categorical data are expressed as percentages of the total observations. The correlation between FFR and iFR was analyzed using Pearson correlation coefficient. The diagnostic performance of iFR in indicating radioisotope (RI) scintigraphy findings of myocardial ischemia was evaluated using receiver operating characteristic (ROC) curve analysis. To achieve an essential diagnostic accuracy for the primary endpoint, as measured by the area under the ROC curve (AUC), while assuming AUC = 0.70, 90.0% power, and a significance level of 0.05 in the 2-sided test, a sample of 80 patients was found to be necessary, consisting of 40 with positive findings on myocardial ischemia perfusion and 40 control subjects. Values of p < 0.05 were considered to indicate statistical significance.
Baseline characteristics of the study population
The baseline patient characteristics are summarized in Table 1. We analyzed data from 95 consecutive patients with symptomatic severe AS who were enrolled in the study between January 2015 and July 2017. The mean patient age was 83 years and 60% of the patients were women. Among the comorbidities, 25% of patients had diabetes mellitus and 67% had chronic renal failure. The median aortic valve area, peak velocity, and mean pressure gradient on echocardiography were 0.60 cm2, 4.40 m/s, and 46.7 mm Hg, respectively. Angiographically, the median lesion length (14.8 mm), mean minimal lumen diameter (1.5 mm), and mean percent of diameter stenosis (47.3%) were determined (Table 2).
Safety of adenosine loading
Adenosine was infused intravenously into a total of 116 vessels to evaluate the FFR. The hemodynamic changes in systolic blood pressure and heart rate after adenosine infusion are shown in Figure 1. Systolic blood pressure fluctuations of more than 40 mm Hg were observed in 12 of 116 vessels (10.3%). The maximal systolic blood pressure fluctuation caused by adenosine infusion was 90 mm Hg. During adenosine infusion, an intermittent atrioventricular block occurred in 1 patient (0.9%), which did not require any treatment and resolved soon after interruption of adenosine infusion. No other major complications, such as bronchospasms, coronary dissections, ventricular arrhythmias, or thrombus formation, occurred (Table 3). The hemodynamic changes during myocardial perfusion scintigraphy are shown in Online Figure 1.
Correlation between IFR and FFR
Figure 2 shows the distribution of iFR and FFR values. Figure 3A shows the relationship between the first and second iFR measurements (iFR 1 and iFR 2), which demonstrated strong reproducibility (R = 0.997; 95% confidence interval [CI]: 0.995 to 0.998; p < 0.0001). Figure 3B shows strong agreement between iFR 1 and FFR (R = 0.854; 95% CI: 0.796 to 0.897; p < 0.0001). Figures 3C and 3D show iFR-FFR agreement in the left anterior descending artery (LAD) and non-LAD lesions (Figure 3C: R = 0.861; 95% CI: 0.785 to 0.911; p < 0.0001) (Figure 3D: R = 0.794; 95% CI: 0.652 to 0.882; p < 0.0001). The ROC curve analysis indicated that the optimal iFR cutoff values corresponding to FFR ≤0.75 and ≤0.80 were 0.82 (AUC: 0.92; p < 0.0001) (Figure 4A) and 0.82 (AUC: 0.89; p < 0.0001) (Figure 4B).
Diagnostic performance of IFR and FFR for indicating RI scintigraphy findings of myocardial ischemia
RI scintigraphy was performed in 78 of the 95 patients. Positive scintigraphy findings of myocardial ischemia were noted in 44 of 116 vessels (intrarater reliability = 0.8798; interrater reliability = 0.8591). The ROC curve analysis for myocardial ischemia detected by adenosine-stress myocardial perfusion imaging indicated that the optimal iFR cutoff value is 0.82 (AUC: 0.84; 95% CI: 0.752 to 0.919; p < 0.0001) (Figure 5A). Figures 5B and 5C show the ROC analysis to indicate myocardial ischemia in the LAD and non-LAD lesions, respectively. The iFR cutoff value indicative of myocardial ischemia was 0.82 in both the LAD and non-LAD lesions (Figure 5B: AUC: 0.82; p < 0.0001) (Figure 5C: AUC: 0.80; p = 0.0001). The relationship between FFR and the scintigraphy findings is shown in Online Figure 2.
The present study demonstrated the diagnostic performance of the iFR in patients with severe AS. The main findings are as follows: 1) iFR has different cutoff values for indicating reversible myocardial perfusion defects in patients with AS than in patients without AS; 2) iFR has excellent reproducibility in patients with AS; 3) there is good correlation between FFR and iFR; and 4) adenosine loading should be performed with careful monitoring.
In patients without AS, FFR cutoff value was set around 0.75 to 0.80 compared with exercise test, thallium scan, and stress echocardiography as the reference standard (15). Historically, research into the benefits of FFR resulted in the FFR versus angiography for multivessel evaluation (FAME) trial. In contrast, the diagnostic performance of FFR and iFR have not been sufficiently explored yet in patients with AS. To the best of our knowledge, this is the first report investigating the diagnostic performance of iFR in patients with severe AS, compared with myocardial perfusion scintigraphy.
In patients without AS, FFR ≤0.75 is associated with myocardial ischemia that can be detected using cardiac scintigraphy (15). Moreover, FFR ≤0.80 can be used in clinical practice to determine the most suitable therapeutic strategy (optimal medical treatment vs. percutaneous coronary intervention). However, both FFR ≤0.80 and iFR ≤0.89 are clinically relevant as predictors of midterm outcome in patients with intermediate coronary artery stenosis (7,8). In the present research, the iFR and FFR values were shown to correlate with myocardial ischemia assessed using perfusion scintigraphy; the values differed depending on the presence or absence of severe AS.
The vasodilatory ability of coronary circulation in AS is blunted by a combination of myocardial hypertrophy, microvascular dysfunction, and raised left ventricular end-diastolic pressure (16). Theoretically, this blunted vasodilator ability results in coronary microvascular impairment. According to previous reports, coronary microvascular impairment in patients with severe AS leads to decreased coronary flow reserve (9,17). Additionally, the hemodynamic characteristics of patients with AS, compared with patients without AS, include lower aortic pressure as consequence of the restricted aortic valve orifice and higher distal coronary pressure caused by left ventricular concentric hypertrophy and increased left ventricular end-diastolic pressure. These potential mechanisms explain the different optimal cutoff values (i.e., the lower iFR and higher FFR values) (10).
A previous report suggested that a reduced coronary flow reserve was present in patients with diabetes mellitus (18). The proposed mechanism involves increased basal coronary flow, which might impact iFR, depending on the stage of diabetes mellitus. However, in the present research, the prevalence of diabetes mellitus was 25.3%, which was similar to that reported in patients involved in the FAME trial (around 25%) (12). Thus, the clinical impact of diabetes mellitus might be limited. In addition, the prevalence of chronic renal failure (67.4%), defined as an estimated glomerular filtration rate <60 ml/min/1.73 m2, was high. The index of microcirculatory resistance was reported to be higher in patients with chronic renal failure, which could be related to FFR (19). Even though the clinical impact of chronic renal failure should be considered, there is limited evidence, to date, regarding its impact, even in patients without AS; further research is needed to elucidate the impact of chronic failure.
Pesarini et al. (20) reported that FFR varies slightly after transcatheter aortic valve replacement (TAVR) and crossed the diagnostic cutoff of 0.8 in a small number of patients after TAVR. However, those FFR measurements were performed immediately after TAVR and may have been affected by periprocedural factors, including anesthesia (either general or local) and high-rate pacing in patients who received prosthetic valve implantation. FFR values could be affected by TAVR procedural techniques in the acute phase. Similarly, in the chronic phase, FFR could be affected by left ventricular remodeling, such as reduced left ventricular mass, improvement in coronary vessel resistance, and vasodilator response.
A previous study reported limited benefits of iFR, which correlated poorly with FFR in patients without AS (21). To investigate the true correlation between FFR and iFR, the ADVISE II (Adenosine Vasodilator Independent Stenosis Evaluation II) trial, a prospective, controlled, core-laboratory-based study, compared the diagnostic accuracy of iFR with that of FFR as a reference standard (6). ADVISE II demonstrated a strong linear correlation between FFR and iFR (R = 0.81; 95% CI: 0.78 to 0.83; p < 0.001). Our research demonstrated a similarly strong correlation between FFR and iFR in patients with severe AS (R = 0.854; p < 0.0001). In addition, excellent reproducibility was observed.
FFR is a functional index tool whose measurement requires a vasodilator. In the specific hemodynamics of patients with severe AS, the administration of a vasodilator raises safety concerns. Although no clinical adverse events, such as ventricular fibrillation or tachycardia, were noted in the present study, the blood pressure of some patients rapidly dropped during adenosine loading (maximum 90 mm Hg) and recovered soon after discontinuation. Temporary atrioventricular block was also observed. These observations illustrate the safety concerns for patients with the specific hemodynamic conditions observed in severe AS. The hemodynamic changes should be carefully monitored during the procedure. However, iFR measurements do not require administration of a vasodilator and, therefore, no additional attention is necessary. In the present research, FFR demonstrated higher AUC than iFR associated with scintigraphy findings. Considering that iFR demonstrated good AUC for indicating myocardial ischemia in patients with AS, iFR measurement could serve as a safe and feasible alternative to FFR measurement in patients with this specific condition.
There are reported differences in the safety concerns associated with adenosine-based assessment methods that depend on the adenosine dosages and administration methods (22). Compared with intravenous adenosine infusion, intracoronary adenosine infusion demonstrates fewer hemodynamic changes during hyperemia. However, another report previously suggested that a conventional dose of intracoronary adenosine is insufficient to induce maximal hyperemia (22). High-dose intracoronary adenosine infusion may not be inferior to intravenous adenosine infusion, but there are side effect concerns in specific conditions, such as in patients with AS. Intracoronary sodium nitroprusside infusion might be another option for reducing hemodynamic changes and side effects, although evidence for this is limited.
The current research demonstrated the potential diagnostic performance of iFR in patients with AS. The optimal iFR cutoff value was suggested to be different, 0.89 to 0.82 for myocardial ischemia when using the reference standards of FFR and myocardial perfusion scintigraphy.
First, coronary angiography was performed without administering nitrates because of the specific hemodynamics of severe AS. Intermediate coronary artery stenosis was evaluated without administering nitrates. Second, the data used for this study were not managed by a core laboratory. Third, the sample size may be considered relatively small. Further investigations are needed to describe the detailed relationship between clinical outcomes and FFR or iFR. Fourth, RI scintigraphy measurements could not be performed in all cases; thus, the analysis of the diagnostic performance of iFR, with respect to RI scintigraphy findings, was performed in 78 of the 95 enrolled patients. Additionally, the adenosine dose (120 μg/kg/min) used during RI scintigraphy was lower than that used for FFR measurements (140 μg/kg/min). Fifth, positron emission tomography can provide more sensitive physiological information than myocardial perfusion scintigraphy. Thus, defining the control group using myocardial perfusion scintigraphy might have underestimated the presence of myocardial ischemia.
The iFR values could be used as a diagnostic tool to indicate myocardial ischemia in patients with AS. The values produced using the technique demonstrate excellent reproducibility and are capable of effectively indicating myocardial ischemia. Considering the hemodynamic changes that occur during adenosine loading in patients with AS, iFR measurements could be safe and feasible indicators of myocardial ischemia in this clinical setting.
WHAT IS KNOWN? FFR represents the standard indicator used in the catheterization laboratory to assess the severity of functional stenosis. iFR has been introduced as an alternative adenosine-free index to assess pressure differences across a stenosed lesion. FFR- and iFR-guided percutaneous coronary interventions did not differ in terms of the 1-year rate of major adverse cardiovascular events.
WHAT IS NEW? The iFR values demonstrated excellent reproducibility and there is good correlation between FFR and iFR values in patients with AS. The present research indicated that iFR has different cutoff values for indicating reversible myocardial perfusion defects in patients with AS, compared with those in patients without severe AS.
WHAT IS NEXT? Considering the hemodynamic changes induced by adenosine loading, iFR could be a useful diagnostic tool for indicating myocardial ischemia.
The authors thank their co-researchers (Etsuko Shimizu, Keiko Asou) from the Clinical Trial Center, Shonan Kamakura General Hospital, Japan for their excellent work.
Dr. Saito is a clinical proctor for Medtronic and Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- aortic valve stenosis
- area under the curve
- confidence interval
- fractional flow reserve
- instantaneous wave-free ratio
- left anterior descending artery
- indicating radioisotope
- receiver operating characteristic
- transcatheter aortic valve replacement
- Received March 21, 2018.
- Revision received July 19, 2018.
- Accepted July 24, 2018.
- 2018 American College of Cardiology Foundation
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