Gabor G. Toth

Prognostic Value of Fractional Flow Reserve: Linking Physiologic Severity to Clinical Outcomes

BACKGROUND Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear. OBJECTIVES The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization. METHODS Meta-analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold. RESULTS A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief. CONCLUSIONS FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy.

Evolving concepts of angiogram: fractional flow reserve discordances in 4000 coronary stenoses

AIMS The present analysis addresses the potential clinical and physiologic significance of discordance in severity of coronary artery disease between the angiogram and fractional flow reserve (FFR) in a large and unselected patient population. METHODS AND RESULTS Between September 1999 and December 2011, FFR and percent diameter stenosis (DS) as assessed by quantitative coronary angiography were obtained in 2986 patients (n = 4086 coronary stenoses), in whom at least one stenosis was of intermediate angiographic severity. Fractional flow reserve correlated slightly but significantly with DS [-0.38 (95% CI: -0.41; -0.36); P < 0.001]. The sensitivity, specificity, and diagnostic accuracy of a ≥ 50% DS for predicting FFR ≤ 0.80 were 61% (95% CI: 59; 63), 67% (95% CI: 65; 69), and 0.64 (95% CI: 0.56; 0.72), respectively. In different anatomical settings, sensitivity and specificity showed marked variations between 35 to 74% and 58 to 76%, respectively, resulting in a discordance in 35% of all cases for these thresholds. For an angiographic threshold of 70% DS, the diagnostic performance by the Youdens index decreased from 0.28 to 0.11 for the overall population. CONCLUSION The data confirm that one-third of a large patient population shows discordance between angiogram ≥ 50%DS and FFR ≤ 0.8 thresholds of stenosis severity. Left main stenoses are often underestimated by the classical 50% DS cut-off compared with FFR. This discordance offers physiologic insights for future trials. It is hypothesized that the discordance between angiography and FFR is related to technical limitations, such as imprecise luminal border detection by angiography, as well as to physiologic factors, such as variable minimal microvascular resistance.

Fractional Flow Reserve–Guided Versus Angiography-Guided Coronary Artery Bypass Graft Surgery

Background— Fractional flow reserve (FFR) is well established for patients undergoing percutaneous coronary intervention, yet little is known about candidates for coronary artery bypass graft surgery. Methods and Results— From 2006 to 2010, we retrospectively included in this registry 627 consecutive patients treated by coronary artery bypass graft surgery having at least 1 angiographically intermediate stenosis. In 429 patients, coronary artery bypass graft surgery was based solely on angiography (angiography-guided group). In 198 patients, at least 1 intermediate stenosis was grafted with an FFR ⩽0.80 or deferred with an FFR >0.80 (FFR-guided group). The end point was major adverse cardiovascular events at 3 years, defined as the composite of overall death, myocardial infarction, and target vessel revascularization. The rate of angiographic multivessel disease was similar in the angiography-guided and FFR-guided groups (404 [94.2%] versus 186 [93.9%]; P=0.722). In the FFR-guided group, this was significantly downgraded after FFR measurements to 86.4% (P<0.001 versus before FFR) and was associated with a smaller number of anastomoses (3 [2–3] versus 3 [2–4]; P<0.001) and rate of on-pump surgery (49% versus 69%; P<0.001). At 3 years, major adverse cardiovascular events were not different between the angiography-guided and FFR-guided groups (12% versus 11%; hazard ratio, 1.030; 95% confidence interval, 0.627–1.692; P=0.908). However, the FFR-guided group compared with the angiography-guided group presented a significantly lower rate of angina (Canadian Cardiovascular Society class II–IV, 31% versus 47%; P<0.001). Conclusions— FFR-guided coronary artery bypass graft surgery was associated with a lower number of graft anastomoses and a lower rate of on-pump surgery compared with angiography-guided coronary artery bypass graft surgery. This did not result in a higher event rate during up to 36 months of follow-up and was associated with a lower rate of angina.

Intracoronary Adenosine: Dose-Response Relationship With Hyperemia.

OBJECTIVES The present study sought to establish the dosage of intracoronary (IC) adenosine associated with minimal side effects and above which no further increase in flow can be expected. BACKGROUND Despite the widespread adoption of IC adenosine in clinical practice, no wide-ranging, dose-response study has been conducted. A recurring debate still exists regarding its optimal dose. METHODS In 30 patients, Doppler-derived flow velocity measurements were obtained in 10 right coronary arteries (RCAs) and 20 left coronary arteries (LCAs) free of stenoses >20% in diameter. Flow velocity was measured at baseline and after 8 ml bolus administrations of arterial blood, saline, contrast medium, and 9 escalating doses of adenosine (4 to 500 μg). The hyperemic value was expressed in percent of the maximum flow velocity reached in a given artery (Q/Qmax, %). RESULTS Q/Qmax did not increase significantly beyond dosages of 60 μg for the RCA and 160 μg for LCA. Heart rate did not change, whereas mean arterial blood pressure decreased by a maximum of 7% (p < 0.05) after bolus injections of IC adenosine. The incidence of transient A-V blocks was 40% after injection of 100 μg in the RCA and was 15% after injection of 200 μg in the LCA. The duration of the plateau reached 12 ± 13 s after injection of 100 μg in the RCA and 21 ± 6 s after the injection of 200 μg in the LCA. A progressive prolongation of the time needed to return to baseline was observed. Hyperemic response after injection of 8 ml of contrast medium reached 65 ± 36% of that achieved after injection of 200 μg of adenosine. CONCLUSIONS This wide-ranging, dose-response study indicates that an IC adenosine bolus injection of 100 μg in the RCA and 200 μg in the LCA induces maximum hyperemia while being associated with minimal side effects.

Revascularization decisions in patients with stable angina and intermediate lesions: Results of the international survey on interventional strategy

Background—Fractional flow reserve (FFR) measurement of intermediate coronary stenoses is recommended by guidelines when demonstration of ischemia by noninvasive testing is unavailable. The study aims to evaluate the penetration of this recommendation into current thinking about revascularization strategies for stable coronary artery disease. Methods and Results—International Survey on Interventional Strategy was conducted via a web-based platform. First, participants’ experiences in interventional cardiology were queried. Second, 5 complete angiograms were provided, presenting only focal intermediate stenoses. FFR and quantitative coronary angiography values were known; however, remained undisclosed. Determination of stenosis significance was asked for each lesion. In cases of uncertainty, the most appropriate adjunctive invasive diagnostic method among quantitative coronary angiography, intravascular ultrasound, optical coherence tomography, or FFR needed to be selected. International Survey on Interventional Strategy was taken by 495 participants who provided 4421 lesion evaluations. In 3158 (71%) decisions, participants relied solely on angiographic appearance that was discordant in 47% with the known FFR, using 0.80 as cutoff value. The use of FFR and imaging modalities was requested in 21% and 8%, respectively. Comparing 4 groups of participants according to the experience in FFR, angiogram-based decisions were less frequent with increasing experience (77% versus 72% versus 69% versus 67%, respectively; P<0.001). As a result, requests for FFR were more frequent (14% versus 19% versus 24% versus 28%, respectively; P<0.001) and rates of discordant decisions decreased (51% versus 49% versus 47% versus 43%, respectively; P<0.022). Conclusions—The findings confirm that, even when all potential external constraints are virtually eliminated, visual estimation continues to dominate the treatment decisions for intermediate stenoses, indicative of a worrisome disconnect between recommendations and current practice.

Significance of Intermediate Values of Fractional Flow Reserve in Patients With Coronary Artery Disease.

Background— The fractional flow reserve (FFR) value of 0.75 has been validated against ischemic testing, whereas the FFR value of 0.80 has been widely accepted to guide clinical decision making. However, revascularization when FFR is 0.76 to 0.80, within the so-called gray zone, is still debatable. Methods and Results— From February 1997 to June 2013, all patients with single-segment disease and an FFR value within the gray zone or within the 2 neighboring FFR strata (0.70–0.75 and 0.81–0.85) were included. Study end points consisted of major adverse cardiovascular events (death, myocardial infarction, and any revascularization) up to 5 years. Of 17 380 FFR measurements, 1459 patients were included. Of them, 449 patients were treated with revascularization and 1010 patients were treated with medical therapy. In the gray zone, the major adverse cardiovascular events rate was similar (37 [13.9%] versus 21 [11.2%], respectively; P=0.3) between medical therapy and revascularization, whereas a strong trend toward a higher rate of death or myocardial infarction (25 [9.4] versus 9 [4.8], P=0.06) and overall death (20 [7.5] versus 6 [3.2], P=0.059) was observed in the medical therapy group. Among medical therapy patients, a significant step-up increase in major adverse cardiovascular events rate was observed across the 3 FFR strata, especially with proximal lesion location. In revascularization patients, the major adverse cardiovascular events rate was not different across the 3 FFR strata. Conclusions— FFR in and around the gray zone bears a major prognostic value, especially in proximal lesions. These data confirm that FFR⩽0.80 is valid to guide clinical decision making.

The Impact of Downstream Coronary Stenosis on Fractional Flow Reserve Assessment of Intermediate Left Main Coronary Artery Disease: Human Validation

OBJECTIVES The aim of this study was to determine the impact of downstream coronary stenosis in the left anterior descending coronary artery (LAD) or left circumflex coronary artery (LCx) on the assessment of fractional flow reserve (FFR) across an intermediate left main coronary artery (LMCA) stenosis in humans with the pressure wire positioned in the nondiseased downstream vessel. BACKGROUND Accurate assessment of intermediate LMCA disease is critical for guiding decisions regarding revascularization. In theory, FFR across an intermediate LMCA stenosis will be affected by downstream disease, even if the pressure wire is positioned in the nondiseased downstream vessel. METHODS After percutaneous coronary intervention of the LAD, LCx, or both, an intermediate LMCA stenosis was created with a deflated balloon catheter. FFR was measured in the LAD and LCx coronary arteries before and after creation of downstream stenosis by inflating an angioplasty balloon within the newly placed stent. The true FFR (FFRtrue) of the LMCA, measured in the nondiseased downstream vessel in the absence of stenosis in the other vessel, was compared with the apparent FFR (FFRapp) measured in the presence of stenosis. RESULTS In 25 patients, 91 pairs of measurements were made, 71 with LAD stenosis and 20 with LCx stenosis. FFRtrue of the LMCA was significantly lower than FFRapp (0.81 ± 0.08 vs. 0.83 ± 0.08, p < 0.001), although the numerical difference was small. This difference correlated with the severity of the downstream disease (r = 0.35, p < 0.001). In all cases in which FFRapp was >0.85, FFRtrue was >0.80. CONCLUSIONS In most cases, downstream disease does not have a clinically significant impact on the assessment of FFR across an intermediate LMCA stenosis with the pressure wire positioned in the nondiseased vessel.

Clinical ResearchCoronaryThe Impact of Downstream Coronary Stenosis on Fractional Flow Reserve Assessment of Intermediate Left Main Coronary Artery Disease: Human Validation

OBJECTIVES The aim of this study was to determine the impact of downstream coronary stenosis in the left anterior descending coronary artery (LAD) or left circumflex coronary artery (LCx) on the assessment of fractional flow reserve (FFR) across an intermediate left main coronary artery (LMCA) stenosis in humans with the pressure wire positioned in the nondiseased downstream vessel. BACKGROUND Accurate assessment of intermediate LMCA disease is critical for guiding decisions regarding revascularization. In theory, FFR across an intermediate LMCA stenosis will be affected by downstream disease, even if the pressure wire is positioned in the nondiseased downstream vessel. METHODS After percutaneous coronary intervention of the LAD, LCx, or both, an intermediate LMCA stenosis was created with a deflated balloon catheter. FFR was measured in the LAD and LCx coronary arteries before and after creation of downstream stenosis by inflating an angioplasty balloon within the newly placed stent. The true FFR (FFRtrue) of the LMCA, measured in the nondiseased downstream vessel in the absence of stenosis in the other vessel, was compared with the apparent FFR (FFRapp) measured in the presence of stenosis. RESULTS In 25 patients, 91 pairs of measurements were made, 71 with LAD stenosis and 20 with LCx stenosis. FFRtrue of the LMCA was significantly lower than FFRapp (0.81 ± 0.08 vs. 0.83 ± 0.08, p < 0.001), although the numerical difference was small. This difference correlated with the severity of the downstream disease (r = 0.35, p < 0.001). In all cases in which FFRapp was >0.85, FFRtrue was >0.80. CONCLUSIONS In most cases, downstream disease does not have a clinically significant impact on the assessment of FFR across an intermediate LMCA stenosis with the pressure wire positioned in the nondiseased vessel.

Standardization of Fractional Flow Reserve Measurements.

Pressure wire-based fractional flow reserve is considered the standard of reference for evaluation of the ischemic potential of coronary stenoses and the expected benefit from revascularization. Accordingly, its application in daily practice or for research purposes has to be as standardized as possible to avoid technical or operator-related artifacts in pressure recordings. This document proposes a standardized way of acquiring, recording, interpreting, and archiving the pressure tracings for daily practice and for the purpose of clinical research involving a core laboratory. Proposed standardized steps enhance the uniformity of clinical practices and data interpretation.

Impact of Right Atrial Pressure on Fractional Flow Reserve Measurements: Comparison of Fractional Flow Reserve and Myocardial Fractional Flow Reserve in 1,600 Coronary Stenoses

OBJECTIVES This study sought to assess the impact of a wide range of mean right atrial pressure (Pra) on fractional flow reserve (FFR) measurements. BACKGROUND FFR invasively assesses the ischemic potential of coronary stenoses. FFR is calculated as the ratio of mean distal coronary pressure (Pd) to mean aortic pressure (Pa) during maximal hyperemia. The Pra is considered to have little impact if it is within normal range, so it is neglected in the formula. METHODS In 1,676 stenoses of 1,235 patients undergoing left-right heart catheterization for ischemic (642 [52%]) or valvular heart disease (593 [48%]), the authors compared the FFR values calculated without accounting for Pra (FFR= Pd/Pa) to the corresponding myocardial fractional flow reserve (FFRmyo) values accounting for Pra (FFRmyo = Pd - Pra/Pa - Pra). RESULTS The median Pra was 7 (interquartile range [IQR]: 5 to 10) mm Hg with a maximum of 27 mm Hg. The correlation and agreement between FFR and FFRmyo was excellent (R(2) = 0.987; slope 1.096 ± 0.003). The median FFR (0.85; IQR: 0.78 to 0.91) was slightly but statistically significantly higher than the median FFRmyo (0.83; IQR: 0.76 to 0.90; p < 0.001) with a median difference of 0.01 (IQR: 0.01 to 0.02). Values of FFR above the cutoff of 0.80 provided an FFRmyo ≤0.80 in 110 (9%) stenoses. No FFR value above 0.80 provided an FFRmyo ≤0.75. CONCLUSIONS The difference between FFR and FFRmyo was minimal even in patients with markedly increased Pra. FFR values above the gray zone (i.e., >0.80) did not yield values below the gray zone (i.e., ≤0.75) in any case, which suggests that the impact of right atrial pressure on FFR measurement is indeed negligible.