• Instantaneous wave-free ratio as an alternative to fractional flow reserve in assessment of moderate coronary stenoses: A meta-analysis of diagnostic accuracy studies

    Abstract

    Background/purpose

    Fractional flow reserve (FFR) remains underutilized due to practical concerns related to the need for hyperemic agents. These concerns have prompted the study of instantaneous wave-free ratio (iFR), a vasodilator-free index of coronary stenosis. Non-inferior cardiovascular outcomes have been demonstrated in two recent randomized clinic trials. We performed this meta-analysis to provide a necessary update of the diagnostic accuracy of iFR referenced to FFR based on the addition of eight more recent studies and 3727 more lesions.

    Methods

    We searched the PubMed, EMBASE, Central, ProQuest, and Web of Science databases for full text articles published through May 31, 2017 to identify studies addressing the diagnostic accuracy of iFR referenced to FFR ≤ 0.80. The following keywords were used: “ instantaneous wave-free ratio ” OR “ iFR ” AND “ fractional flow reserve ” OR “ FFR .”

    Results

    In total, 16 studies comprising 5756 lesions were identified. Pooled diagnostic accuracy estimates of iFR versus FFR ≤ 0.80 were: sensitivity, 0.78 (95% CI, 0.76–0.79); specificity, 0.83 (0.81–0.84); positive likelihood ratio, 4.54 (3.85–5.35); negative likelihood ratio, 0.28 (0.24–0.32); diagnostic odds ratio, 17.38 (14.16–21.34); area under the summary receiver-operating characteristic curve, 0.87; and an overall diagnostic accuracy of 0.81 (0.78–0.84).

    Conclusions

    In conclusion, iFR showed excellent agreement with FFR as a resting index of coronary stenosis severity without the undesired effects and cost of hyperemic agents. When considering along with its clinical outcome data and ease of application, the diagnostic accuracy of iFR supports its use as a suitable alternative to FFR for physiology-guided revascularization of moderate coronary stenoses.

    Summary

    We performed a meta-analysis of the diagnostic accuracy of iFR referenced to FFR. iFR showed excellent agreement with FFR as a resting index of coronary stenosis severity without the undesired effects and cost of hyperemic agents. This supports its use as a suitable alternative to FFR for physiology-guided revascularization of moderate coronary stenoses.

    Highlights

     

    •  

      iFR shows excellent agreement with FFR with an overall diagnostic accuracy of 81%.

    •  

      iFR has noninferior cardiovascular outcomes compared to FFR.

    •  

      iFR provides a practical alternative to FFR without the need for hyperemic agents.

     

    Introduction

    Physiologic methods to guide coronary revascularization can identify hemodynamically significant stenoses and improve cardiovascular (CV) outcomes  . Fractional flow reserve (FFR) has become the invasive reference standard for physiologic guidance based on extensive investigation and improved clinical outcomes compared to angiographic-guided revascularization  . Despite guideline-based recommendations, FFR is underutilized likely due to side effects from hyperemic agents, prolonged procedure time, and increased cost  . These issues have prompted study of the instantaneous wave-free ratio (iFR), a vasodilator-free index of coronary stenosis. iFR represents the gradient across a coronary lesion during a period of diastole when coronary flow is not impacted by compression or decompression of the microcirculation and distal resistance is constant and minimized  . During the wave-free period, intracoronary blood flow correlates linearly with intracoronary pressure thereby allowing approximation of flow differences without the need for hyperemia  . The randomized trials DEFINE-FLAIR and iFR SWEDEHEART have demonstrated noninferior cardiovascular (CV) outcomes with an iFR-guided compared to a FFR-guided strategy, and a previous meta-analysis has suggested a comparable diagnostic accuracy of iFR to FFR  . Here, our meta-analysis provides a needed update with the addition of eight more recent studies and examines the overall diagnostic accuracy of iFR referenced to FFR .

    Methods

    We conducted this meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, in accordance with best practice guidelines. Authors had full access to all the study information and take responsibility for the integrity of the results.

    Literature search strategy and study identification

    A comprehensive literature search of the PubMed, EMBASE, Central, ProQuest, and Web of Science databases through May 31, 2017 was independently performed by two reviewers (RM, JM) to identify studies comparing the diagnostic accuracy of iFR, using FFR as a reference, for the assessment of physiologically significant coronary stenoses. The following keywords were utilized in the search: “ instantaneous wave-free ratio ” OR “ iFR ” AND “fractional flow reserve ” OR “ FFR ”, without language restrictions. Composite variations of each search term were also considered. All retrieved studies were carefully examined. Inconsistencies were discussed by the reviewers and any disagreement was resolved by consensus or referral to a third reviewer. A final list of studies was approved by all authors and any potential overlapping data were omitted. The procedure of informed consent and institutional board review was not applicable.

    Study eligibility

    The studies selected for inclusion met the following criteria: (a) iFR was considered as the index test and FFR as the reference and (b) the diagnostic accuracy statistics provided sufficient data to construct 2 × 2 contingency tables. Studies were excluded if: (a) multiple reports were published for the same study population and (b) reports provided insufficient data for the outcomes to be analyzed.

    Quality assessment and data extraction

    The methodological quality of the included studies was assessed using the revised tool for the quality assessment of diagnostic accuracy studies (QUADAS-2) by two separate observers. This is a quality assessment instrument specifically developed for systematic reviews of diagnostic accuracy studies. Each item was scored as ‘yes’ or ‘no’, or ‘unclear’ if there was insufficient information to make an accurate judgement.

    We collected baseline characteristics from each selected study. In addition, the following characteristics were documented: first author, publication year, sample size, description of study population, and study design. To perform pooled accuracy analyses, values of true positive (TP), false positive (FP), false negative (FN), true negative (TN), sensitivity, specificity, area under the summary receiver-operating characteristic curve (AUC), positive and negative predictive values, and positive and negative likelihood ratio (LR +, LR-, respectively) for the detection of lesions were extracted and 2 × 2 contingency tables were constructed.

    Statistical analysis

    Heterogeneity was assessed using the Cochran's test and the Higgins I heterogeneity index. A significant Qtest ( < 0.05) is suggestive of the presence of heterogeneity. The I index, a measure of the percentage of total variation across studies that is due to heterogeneity (beyond sampling variation), was classified as not likely (I 2= 0–30%), moderately (I = 30–50%), or substantially (I > 50%) contributory to heterogeneity. Considering the general characteristics of the sampled universe and the difference in true effect size across the studies included in this analysis, a random-effects model was utilized over the fixed [common]-effect model. Between-study variance in the random-effects meta-analysis was further estimated using the Tau test. A Tau > 1 is suggestive of substantial statistical heterogeneity.

    The statistical computations were performed using the R Project for Statistical Computing software to pool sensitivity, specificity, diagnosis odds ratio (DOR), LR + and LR − with 95% confidence intervals (CIs), respectively. If heterogeneity was detected, existence of a threshold effect was calculated based on the Spearman correlation coefficient between the logit of sensitivity and the logit of (1-specificity). Summary receiver-operating characteristic curves (SROC) were constructed to determine the pooled diagnostic accuracy capabilities utilizing the Moses-Shapiro-Littenberg methodology. A meta-regression analysis was performed by the DOR by adding predetermined variables (age, sex, diabetes, hypertension, and smoking habit) as covariates to the Mose-Shapiro-Littenberg model. Further meta-regression analysis was performed on the DOR using stable and unstable angina as covariates. The results were regarded as statistically significant at a 2-sided < 0.05.

    Assessment of publication bias

    Publication bias was assessed using a modified Deek's test based on sensitivity values and sample size, which was performed to test asymmetries of the funnel plots. This is a scatter plot of the inverse of the square root of the effective sample size (1/ESS1/2) versus the diagnostic log odds ratio. A significant regression coefficient ( < 0.05) indicates an association between sample size and sensitivity, suggestive of publication bias.

    Results

    Search results

    The initial database search retrieved 475 potentially relevant publications. The selection of studies was conducted according to the PRISMA statements. After removing 197 duplicates, 278 studies were screened by title and abstract. Of these, 54 full-text articles remained to assess for eligibility. Finally, a total of 16 studies met the inclusion criteria and were included in the meta-analysis. A flowchart of the search and selection process of the studies is shown in Fig. 1 

    Fig. 1
    Flow diagram of search and study selection. FFR: fractional flow reserve.

     

    Description of the included trials

    Baseline characteristics of these studies and the subjects are shown in Tables 1-3 . Briefly, this meta-analysis was based on 16 nonrandomized, observational, prospective, diagnostic performance studies (nine multicenter, seven single center) that included 5756 lesions (range per trial 123 to 1593). Mean age ranged from 62 to 70 years old; male sex: 64% to 83%; diabetes: 17% to 41%; smoking: 22% to 69%; hypertension: 56% to 81%; stable angina: 35% to 96%; unstable angina: 4% to 65%; single vessel disease: 36% to 100%; multivessel disease: 0% to 63%; left anterior descending artery: 0% to 100%; left circumflex artery: 0% to 27%; right coronary artery: 0% to 29%; intravenous adenosine: 0% to 100%; and intracoronary adenosine: 0% to 100%. 

    Table 1
    Summary characteristics of included studies.
    StudyPublished year# of lesionsDesignInclusion criteriaExclusion criteriaFfr acutoffIfr bcutoff
    ADVISE 2011 157 Multicenter, nonrandomized, observational, prospective Patients with coronary stenosis Valvular diseases, previous CABG , contraindication to adenosine, increased troponin, and overweight 0.8 0.83
    VERIFY 2013 206 Multicenter, nonrandomized, observational, prospective Patients with coronary stenosis required functional intracoronary assessment Prior CABG, extremely tortuous, calcified lesions, coronary artery occlusion, acute MI within 5 days 0.8 0.83
    Park et al. 2013 238 Multicenter, nonrandomized, observational, prospective Patients with coronary stenosis required functional intracoronary assessment In-stent restenosis, acute ST-segment elevation myocardial infarction, chronic total occlusion lesions, vessels with collateral feeders, regional wall motion abnormalities of a target vessel segment, left ventricular ejection fraction < 40%, primary myocardial or valvular disease, contraindication to adenosine, or angiographically visible thrombus of a target lesion 0.8 0.9
    ADVISE In PRACTICE 2014 392 Multicenter, nonrandomized, observational, prospective Patients with coronary stenosis required functional intracoronary assessment Previous CABG, contraindication to adenosine administration 0.8 0.9
    Indolfi et al. 2014 123 Single center, nonrandomized, observational, prospective Patients referred for coronary angiography who had multivessel disease with at least one intermediate stenosis in setting of ACS e Noncardiac life-threatening disease, requiring valvular surgery, cardiologist decided not to perform FFR to guide the treatment, hemodynamic instability, ongoing arrhythmias, valve disease, contraindication to adenosine administration 0.8 0.92
    ADVISE 2 2015  2015 690 Multicenter, nonrandomized, observational, prospective, double blind Patients with coronary stenosis required functional intracoronary assessment Previous CABG, contraindication to adenosine administration, increased troponin, and overweight 0.8 0.89
    Harle et al. 2015 151 Single center, nonrandomized, observational, prospective Patients with coronary stenosis required functional intracoronary assessment Contraindications to adenosine administration 0.8 0.896
    Shiode et al.  2016 123 Single center, nonrandomized, observational, prospective Mild or moderate stenosis who were undergoing coronary angiography 0.8 0.89
    Kobayashi et al. (LM f/pLAD ) 2016 201 Multicenter, nonrandomized, observational, prospective 18 years or older who underwent invasive physiological assessment of coronary artery lesions for standard clinical indications Previous CABG, an extremely tortuous or calcified coronary artery, known severe LVH , left ventricular ejection fraction < 30%, inability to receive adenosine, renal insufficiency such that additional contrast would pose unwarranted risk, or recent (within 3 weeks before cardiac catheterization) ST-segment elevation myocardial infarction 0.8 0.9
    Kobayashi et al. (other lesions) 2016 559 Multicenter, nonrandomized, observational, prospective 18 years or older who underwent invasive physiological assessment of coronary artery lesions for standard clinical indications Previous CABG, an extremely tortuous or calcified coronary artery, known severe LVH, left ventricular ejection fraction < 30%, inability to receive adenosine, renal insufficiency such that additional contrast would pose unwarranted risk, or recent (within 3 weeks before cardiac catheterization) ST-segment elevation myocardial infarction 0.8 0.9
    VERIFY 2 2016 257 Single center, nonrandomized, observational, prospective 18–90 years old with angiographically intermediate coronary stenoses in which FFR measurement was clinically indicated Severe calcific coronary disease, severe tortuosity rendering pressure wire studies difficult or impossible, recent myocardial infarction within 72 h, ongoing unstable chest pain, known intolerance of adenosine, or severe asthma 0.8 0.9
    Meimoun et al.  2016 94 Single center, nonrandomized, observational, prospective Stable CAD with 50–70% intermediate LAD jstenosis Hemodynamic instability, acute coronary syndrome involving the LAD as a culprit vessel, contra indication to adenosine, a stenosis in the distal part of the LAD, and two or more stenoses in the LAD 0.8 0.88
    Johnson et al.  2016 763 Multicenter, nonrandomized, observational, prospective Undergoing routine FFR assessment for standard indications Previous coronary bypass surgery, known severe cardiomyopathy (left ventricular ejection fraction < 30%) or left ventricular hypertrophy (septal wall thickness > 13 mm), contraindication to adenosine, or renal insufficiency such that an additional 12 to 20 mL of contrast would pose an unwarranted risk 0.8 0.9
    Kanaji et al.  2016 120 Single center, nonrandomized, observational, prospective Undergoing coronary angiography for suspected coronary artery disease with lesions in at least one epicardial proximal coronary artery that were angiographically intermediate (30–80% by visual estimation) History of CABG, tortuous coronary arteries, severely calcified arteries, acute coronary syndrome, history of myocardial infarction, occluded coronary arteries, left main disease, coronary ostial stenosis, congestive heart failure, significant arrhythmias, renal insufficiency (creatinine 1.5 mg/dL), or absolute contraindication to adenosine 0.8 0.89
    Fede et al. 2015 89 Single center, nonrandomized, observational, prospective Undergoing coronary angiography for stable or unstable angina, or for non ST elevation myocardial infarction found to have intermediate stenosis of 50–70% by visual estimation ST-segment elevation myocardial infarction or hemodynamic unstable conditions 0.8 0.89
    RESOLVE 2014 1593 Multicenter, nonrandomized, observational, retrospective Patients with stable angina, unstable angina, or non ST-segment myocardial infarction undergoing coronary angiography with or without percutaneous coronary intervention in whom FFR of a single stenosis in a major epicardial coronary artery was performed during the procedure Left main disease, heart failure as defined by New York Heart Association class III or IV, respiratory failure requiring intubation or supplementary oxygen, cardiogenic shock, significant arrhythmia precluding waveform analysis (examples include premature ventricular contractions or atrial fibrillation), and tachycardia with heart rate > 120 beats/min 0.8 0.9

    a FFR: fractional flow reserve.

    b IFR: instantaneous wave-free ratio.

    c CABG: Coronary artery bypass grafting.

    d MI: myocardial infarction.

    e ACS: acute coronary syndrome.

    f LM: left main artery.

    g pLAD: proximal left anterior descending artery.

    h LVH: left ventricular hypertrophy.

    i CAD: coronary artery disease.

    j LAD: left anterior descending.

    Table 2
    Baseline data and cardiovascular risk factors of study population.
    StudyAgeMale (%)Smoking (%)Diabetes (%)Hypertension (%)Stable angina (%)Unstable angina (%)
    ADVISE  62.6 ± 10.2 131 (83) 34 (22) 54 (34) 88 (56) 151 (96) 6 (4)
    VERIFY  65.2 ± 10.2 146 (71) 64 (31) 50 (24) 137 (67) 140 (68) 46 (22)
    Park et al.  62.8 ± 0.6 161 (68) 64 (27) 66 (28) 133 (56) 151 (63) 84 (36)
    ADVISE In PRACTICE  67 ± 11 247 (79) 160 (51) 94 (30) 232 (74) 228 (73) 85 (27)
    Indolfi et al.  64 ± 9 67 (82) 49 (60) 14 (17) 61 (74) 29 (35) 53 (65)
    ADVISE 2  63.6 ± 10.8 412 (69) 135 (23) 209 (35) 471 (78.8) 320 (54) 151 (25)
    Harle et al.  67 ± 11 69 (64)
    Shiode et al.  70.4 ± 8.7 77 (74.8) 28 (27.1) 40 (39) 82 (80) 92 (89.3)
    Kobayashi et al. (LM a/pLAD  66 (58–72) 141 (70.1) 87 (43.3) 47 (23.4) 138 (68.7) 160 (79.6)
    Kobayashi et al. (other lesions)  67 (58–73) 406 (72.6) 276 (49.4) 131 (23.4) 406 (72.6) 435 (77.8)
    VERIFY 2  136 (69) 48 (24.4) 31 (15.7) 123 (62.4) 129 (50.1) 18 (7)
    Meimoun et al.  68 ± 10 75 (80) 36 (38) 29 (31) 53 (56) 71 (76)
    Johnson et al.  66 ± 10 547 (72) 363 (48) 219 (29) 545 (71) 598 (78) 84 (11)
    Kanaji et al.  66.6 ± 10.3 94 (79.3) 83 (69.2) 49 (40.8) 80 (63.8)
    Fede et al.  67 ± 11 41 (76) 14 (26) 44 (81) 36 (66) 9 (17)
    RESOLVE  63.4 ± 10.3 1193 (74.9) 468 (29.4) 448 (28.1) 1093 (68.6) 229 (14.4)

    a LM: left main artery.

    b pLAD: proximal left anterior descending artery.

    Table 3
    Baseline angiographic and procedural characteristics.
    StudySingle vessel (%)Multi-vessel (%)Lad a(%)Lcx b(%)Rca c(%)Iv adenosine (%) Ic adenosine (%) 
    ADVISE  108 (69) 49 (31) 69 (44) 43 (27) 45 (29) 63 (40) 94 (60)
    VERIFY  85 (41) 105 (51) 133 (64) 28 (14) 45 (22) 206 (100) 0 (0)
    Park et al.  173 (73) 238 (100) 238 (100)
    ADVISE In PRACTICE  141 (36) 247 (63) 259 (66) 39 (10) 55 (14) 153 (39) 239 (61)
    Indolfi et al.  18 (15) 123 (100) 0 (0)
    ADVISE 2  380 (55) 179 (26) 138 (20) 690 (100) 0 (0)
    Harle et al.  75 (69) 33 (31) 66 (44) 20 (13) 42 (28) 138 (91) 13 (9)
    Shiode et al.  90 (73) 4 (3) 29 (24) 0 (0) 123 (100)
    Kobayashi et al. (LM f/pLAD  201 (100) 0 (0) 0 (0) 201 (100) 201 (100)
    Kobayashi et al. (other lesions)  0 (0) 559 (100) 559 (100)
    VERIFY 2  148 (58) 37 (14) 45 (18) 257 (100) 0 (0)
    Meimoun et al.  94 (100) 0 (0) 94 (100) 0 (0) 0 (0) 0 (0) 94 (100)
    Johnson et al.  460 (60) 138 (18) 140 (18) 315 (72) 124 (28)
    Kanaji et al.  89 (74) 31 (26) 77 (64) 16 (13) 27 (23) 120 (100) 0 (0)
    Fede et al.  52 (58) 20 (23) 17 (19) 0 (0) 89 (100)
    RESOLVE  736 (46) 857 (54) 1004 (63) 271 (17) 319 (20) 1276 (80) 317 (20)

    a LAD: left anterior descending artery.

    b LCx: left circumflex artery.

    c RCA: right coronary artery.

    d IV: intravenous.

    e IC: intracoronary.

    f LM: left main artery.

    g pLAD: proximal left anterior descending artery.

     Multiple studies used both intravenous and intracoronary adenosine in same lesion.

     

    Quality assessment and publication bias

    The overall methodological quality of the included studies, according to the QUADAS-2 assessment, varied from moderate to high in our study. Deeks' asymmetry test did not show association between the sample size and sensitivity values ( > 0.05 for all), which suggest absence of publication bias.

    Diagnostic accuracy of iFR

    As depicted in Table 4 and Fig. 2 , the pooled diagnostic accuracy estimates of iFR versus FFR ≤ 0.80 were: sensitivity, 0.78 (95% CI, 0.76–0.79); specificity, 0.83 (0.81–0.84); positive likelihood ratio, 4.54 (3.85–5.35); negative likelihood ratio, 0.28 (0.24–0.32); diagnostic odds ratio, 17.38 (14.16–21.34), and an overall diagnostic accuracy of 0.81 (0.78–0.84). The AUC for iFR was 0.87 ( Fig. 3 ). However, significant heterogeneity existed between the studies for sensitivity (I = 70%), specificity (74.8%), DOR (41.7%), LR + (70%), and LR − (73.1%). 

    Table 4
    Pooled diagnostic accuracy measures of iFR referenced to FFR .
    MeasureValue (95% CI )
    Diagnostic accuracy 0.81 (0.78–0.84)
    Sensitivity 0.78 (0.76–0.79)
    Specificity 0.83 (0.81–0.84)
    Positive likelihood ratio 4.54 (3.85–5.35)
    Negative likelihood ratio 0.28 (0.24–0.32)
    Diagnostic odds ratio 17.38 (14.16–21.34)

    a iFR: instantaneous wave-free ratio.

    b FFR: fractional flow reserve.

    c CI: confidence interval.

    Fig. 2
    Forest plots for sensitivity, specificity, LR +, LR-, and DOR of iFR referenced to FFR ≤ 0.80. CI: confidence interval. LR: likelihood ratio. OR: odds ratio.
    Fig. 3
    Summary receiver-operating characteristic curve for iFR using random-effects model. sROC: summary receiver-operating characteristic curve. SE: standard error. AUC: area under sROC. Q: result of Cochran's Q test.

     

    Diagnostic threshold effect

    A Spearman's rank correlation was performed to evaluate for the presence of a threshold effect. The Spearman's correlation coefficient was 0.678 ( = 0.08) indicating the possibility of a threshold effect. The positive value indicates that the thresholds increase sensitivity at the expense of specificity. This could be explained by the different cutoff values used in the various studies. Therefore, a symmetrical sROC curve was drawn.

    Meta-regression analysis

    The meta-regression analysis, using the predefined potential sources of heterogeneity as covariates in the Moses–Shapiro–Littenberg model, indicated that the iFR cut-off value ( < 0.05) might be a significant predictor. Other factors did not influence the diagnostic accuracy, including age ( = 0.72), sex ( = 0.48), the prevalence of diabetes ( = 0.57), hypertension ( = 0.48), and smoking habit ( = 0.18). A meta-regression on DOR with percent stable angina (B = 0.15, CI = − 1.1 to 1.4, = 0.82) and unstable angina (B = − 0.09, CI − 1.03 to − 0.86) cases as covariates demonstrated no significant association with diagnostic outcome.

    Discussion

    There has been a sizeable amount of diagnostic accuracy data published since a previous meta-analysis on this topic  . The aim of our meta-analysis is to provide a fully updated, robust summary on the functional correlation of iFR to FFR and to determine if significant limitations in the value of iFR are present. We performed a more rigorous analysis of more than twice the number of studies and lesions with addition of eight studies and 3727 lesions  . Our meta-analysis demonstrates that iFR as a resting index of coronary stenosis severity has excellent agreement with FFR and is a suitable alternative to FFR for physiologic assessment of coronary artery disease.

    To consider any physiologic measurement as an alternative to FFR, functional correlation must be demonstrated. Our meta-analysis of 16 studies depicts the functional correlation of iFR to FFR by demonstrating an overall diagnostic accuracy of 81%. As a point of context, these results parallel the overall 83% diagnostic accuracy of FFR values referenced to noninvasive stress testing  . Of course, mismatch will exist as both tests likely have their own idiosyncratic benefits and limitations in accurately diagnosing ischemia, similar to non-invasive testing  . Of note, when mismatch occurs, iFR correlates with myocardial perfusion imaging in half of cases but FFR correlates in the other half of cases  . The mismatch may be the result of specific procedural characteristics of the different measurements. FFR encompasses the entire cardiac cycle including systole when intracoronary resistance is most dynamic and averages multiple beats including ectopy  . iFR, on the other hand, excludes systole and measures the trans-stenotic gradient during the wave-free period of diastole for an individualized beat, thus avoiding systolic and whole-cycle variation potentially resulting in different results from FFR. Additionally, for patients with normal iFR in the setting of high resting microvascular resistance and normal coronary flow reserve, hyperemia may produce an abnormal FFR due to microvascular vasodilation creating a discrepancy between the two measurements  . The reverse phenomenon of abnormal iFR and normal FFR also seems to occur in the presence of significant microvascular dysfunction and an inability to vasodilate appropriately after adenosine administration, particularly in the presence of diabetes mellitus  . While FFR is considered the invasive reference standard, positron emission tomography (PET) is the accepted non-invasive gold standard for ischemia  . The diagnostic accuracy of iFR and FFR appears similar for PET-derived coronary flow reserve, suggesting that the mismatch observed in invasive diagnostic accuracy studies may not be clinically impactful  . Interestingly, however, iFR seems to have better correlation to invasively-derived CFR, perhaps hinting at a superiority of iFR or, at the very least, supporting its function as an acceptable alternative . Lastly, when comparing two categorical variables, values near the dichotomous cut-off can be nearly identical but still result in mismatch.

    Despite endorsement from clinical practice guidelines, FFR has been significantly underutilized in clinical practice due to several practical considerations  . iFR eases these concerns with significantly reduced procedure times, less patient dissatisfaction, and fewer stents placed while still maintaining noninferiority  . For patients with multivessel disease, operators are more likely to evaluate lesions with iFR than FFR presumably due to easier procedural setup and the ability to evaluate lesions in series without a pullback/losing wire positioning  . Since use of iFR results in more deferred lesions, it is important to confirm its safety. In stable ischemic heart disease, there is no significant difference in outcomes at one year of deferred lesions using iFR compared to FFR  . Furthermore, in acute coronary syndromes, deferral of lesions based on iFR appears to result in better outcomes than FFR  . When considered along with practicality and safety outcomes, the consistent diagnostic accuracy demonstrated in our meta-analysis supports the characterization of iFR as a well-suited physiologic alternative to FFR that could lead to increased utilization in the invasive lab.

    Our meta-analysis has several limitations. Besides a considerable degree of heterogeneity for the pooled sample, the validity of our results is dependent on the validity of the included diagnostic accuracy studies. Differences in iFR cutoff values, varying acquisition protocols, and nonuniform patient and lesion characteristics at each site have likely introduced inaccuracy into our results. Of the 16 studies, 14 used an iFR cutoff value between 0.89 and 0.92 while the remaining two used a lower cut-off of 0.83. Interestingly, three of the 16 studies found substantially lower diagnostic accuracy compared to the other studies  . Upon review, two of those three trials isolated patients with stenoses responsible for larger myocardial territories including left main (LM) and proximal left anterior descending artery (LAD) disease  . For LM or proximal LAD lesions, the change in coronary flow with hyperemia may be greater when compared to vessels supplying smaller amounts of myocardium possibly resulting in a larger pressure gradient and lower FFR  . In this study, the discordance between Pd/Pa and FFR was greatest for LM and proximal LAD lesions compared with other lesion locations. The third study documented considerable variability of heart rate and blood pressure impacting the accuracy and reproducibility of both iFR and FFR  . Finally, we may have been unable to identify all the sources of heterogeneity among the included studies by meta-regression because of the limited data reported.

    Conclusions

    iFR as a resting index of coronary stenosis severity shows excellent agreement with FFR without the undesired side effects, increased procedural time, and cost of hyperemic agents. Our meta-analysis provides the largest, comprehensive assessment of the diagnostic accuracy of iFR while recent outcome trials have demonstrated its clinical utility. Therefore, iFR has significant merit as a suitable stand-alone measure for physiology-guided revascularization of moderate coronary stenoses.

    Acknowledgements

    None. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

    Author bio

    Cardiovascular Revascularization Medicine, 2018-07-01, Volume 19, Issue 5, Pages 613-620, Copyright © 2017

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