Luigi Di Serafino

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.

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.

Long-term clinical outcome after fractional flow reserve- versus angio-guided percutaneous coronary intervention in patients with intermediate stenosis of coronary artery bypass grafts.

BACKGROUND Fractional flow reserve (FFR)-guided percutaneous revascularization (percutaneous coronary intervention [PCI]) of intermediate stenosis in native coronary artery is safe and associated with better clinical outcomes as compared with an angiography-guided PCI. It is unknown whether this applies to coronary artery bypass grafts (CABGs). METHODS We included 223 patients with CABG and with stable or unstable angina and an intermediate stenosis involving an arterial or a venous graft. Patients were divided into 2 groups: FFR guided (n = 65, PCI performed in case of FFR ≤0.80) and angio guided (n = 158, PCI performed based on angiographic evaluation). Primary end point was major adverse cardiac and cerebrovascular event, defined as death, myocardial infarction, target vessel failure, and cerebrovascular accident (CVA). RESULTS The 2 groups were similar in terms of demographic and clinical characteristics. Percutaneous coronary intervention was performed in 23 patients (35%) of the FFR-guided group and 90 patients (57%) of the angio-guided group (P < .01). In the FFR-guided group, PCI was more often performed in arterial grafts as compared with the angio-guided group (16 [70%] vs 12 [13%], respectively; P < .01). Follow-up was obtained in 96% of patients at a median of 3.8 years (1.6-4.0 years). At multivariate analysis, major adverse cardiac and cerebrovascular event rate was significantly lower in the FFR-guided group as compared with the angio-guided group (18 [28%] vs 77 [51%], hazard ratio 0.33 [0.11-0.96], P = .043]. Procedure costs were overall reduced in the FFR-guided group (€2240 ± €652 vs €2416 ± €522, P = .03). CONCLUSIONS An FFR-guided PCI of intermediate stenosis in bypass grafts is safe and results in better clinical outcomes as compared with an angio-guided PCI. This clinical benefit is achieved with a significant overall reduction in procedural costs.

Intracoronary Enalaprilat to Reduce Microvascular Damage During Percutaneous Coronary Intervention (ProMicro) Study

OBJECTIVES This study investigated the influence of intracoronary enalaprilat on coronary microvascular function and peri-procedural outcome measures in patients with stable angina undergoing percutaneous coronary intervention (PCI). BACKGROUND Intracoronary angiotensin-converting enzyme inhibitors have been shown to relieve myocardial ischemia in stable patients and to improve epicardial flow in patients with ST-segment elevation myocardial infarction. Yet, it is still unclear whether these effects are mediated by a modulation of the coronary microcirculation. METHODS We randomly assigned 40 patients to receive either an intracoronary bolus of enalaprilat (50 μg) or placebo before elective PCI. The index of microvascular resistance was measured at baseline, 10 minutes after study drug administration, and after PCI. High-sensitivity cardiac troponin T was measured as a marker of myocardial injury. RESULTS Infusion of enalaprilat resulted in a significant reduction in index of microvascular resistance (27 ± 11 at baseline vs. 19 ± 9 after drug vs. 15 ± 8 after PCI), whereas a significant post-procedural increase in index of microvascular resistance levels was observed in the placebo group (24 ± 15 at baseline vs. 24 ± 15 after drug vs. 33 ± 19 after PCI). Index of microvascular resistance levels after PCI were significantly lower in the enalaprilat group (p < 0.001). Patients pre-treated with enalaprilat also showed lower peak values (mean: 21.7 ng/ml, range: 8.2 to 34.8 ng/ml vs. mean: 32.3 ng/ml, range: 12.6 to 65.2 ng/ml, p = 0.048) and peri-procedural increases of high-sensitivity cardiac troponin T (mean: 9.9 ng/ml, range: 2.7 to 19.0 ng/ml vs. mean: 26.6 ng/ml, range: 6.3 to 60.5 ng/ml, p = 0.025). CONCLUSIONS Intracoronary enalaprilat improves coronary microvascular function and protects myocardium from procedure-related injury in patients with coronary artery disease undergoing PCI. Larger studies are warranted to investigate whether these effects of enalaprilat could result into a significant clinical benefit.

Effects of successful percutaneous lower extremity revascularization on cardiovascular outcome in patients with peripheral arterial disease

BACKGROUND Lower extremity peripheral arterial disease (LE-PAD) reduces walking capacity and is associated with an increased cardiovascular risk. Endovascular revascularization of LE-PAD improves walking performance and quality of life. In the present study, we determined whether successful lower limbs revascularization also impacts cardiovascular outcome in LE-PAD patients. METHODS 479 consecutive LE-PAD patients at stage II of Fontaines classification, with ankle/brachial index ≤ 0.90 and one or more stenosis >50% in at least one leg artery, were enrolled in the study. According to the Trans-Atlantic Inter Society Consensus II recommendations, 264 (55.1%) underwent percutaneous lower extremity angioplasty (PTA group), while 215 (44.9%) were managed with conservative therapy (MT group). The incidence of major cardiovascular events (including cardiovascular death, myocardial infarction, ischemic stroke, coronary and carotid revascularizations) was prospectively analyzed by Kaplan-Meier curves. Crude and adjusted HRs (95% CI) of developing a cardiovascular event were calculated by Cox analysis. RESULTS No baseline differences were observed among the groups, except for a lower maximum walking distance in the PTA group. During a median follow-up of 21 months (12.0-29.0), the incidence of cardiovascular events was markedly lower in PTA compared to MT patients (6.4% vs. 16.3%; p=0.003), and patients in the MT group showed a 4.1-fold increased cardiovascular risk compared to patients in the PTA group, after adjustment for potential confounders (95% CI 1.22-13.57, p=0.023). CONCLUSIONS This study shows that successful revascularization of LE-PAD patients affected by intermittent claudication, in addition to improving functional status, reduces the occurrence of future major cardiovascular events.

Contrast-induced nephropathy in patients undergoing primary percutaneous coronary intervention without acute left ventricular ejection fraction impairment.

The prognostic relevance of direct contrast toxicity in patients treated with primary percutaneous coronary intervention remains unclear, owing to the confounding hemodynamic effect of acute left ventricular ejection fraction (LVEF) impairment on kidney function estimation. In the present study, 644 consecutive patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention were prospectively enrolled. Contrast-induced nephropathy (CIN) was defined as an increase in serum creatinine >25% or a decrease in the estimated glomerular filtration rate (eGFR) <25% from baseline in the first 72 hours. The primary end point of the study was major adverse cardiovascular events at 1 year (composite of death, myocardial infarction, target lesion revascularization, and bleeding). Among the global population, the interaction between the LVEF and eGFR at admission to define CIN was statistically significant (p <0.001). When only the 385 patients without acute LVEF impairment (i.e., those with LVEF ≥40%) were considered, 27 (7%) developed postprocedural CIN that was associated with increased major adverse cardiovascular events rate at 1 year of clinical follow-up (38% vs 9%; p <0.001). On adjusted Cox multivariate analysis, CIN was an independent predictor of worse outcomes, both when defined according to creatinine (hazard ratio 3.81, 95% confidence interval 1.71 to 8.48, p = 0.001) or eGFR (hazard ratio 3.77, 95% confidence interval 1.53 to 9.28, p = 0.004) variations. In conclusion, in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention, LVEF has a significant interaction with eGFR. When only patients without acute LVEF impairment were considered, CIN confirmed its negative prognostic effect on the 1-year clinical outcomes.

Quantitative angiography and optical coherence tomography for the functional assessment of nonobstructive coronary stenoses: comparison with fractional flow reserve.

BACKGROUND The purpose was to compare 3-dimensional quantitative coronary angiography (3D-QCA) with optical coherence tomography (OCT) for the functional assessment of nonobstructive coronary stenoses, as evaluated by fractional flow reserve (FFR). METHODS Fifty-five nonobstructive coronary stenoses (30%-50% diameter stenosis by visual estimation) were assessed in 36 patients using FFR, 2-dimensional QCA (2D-QCA), 3D-QCA, and OCT. RESULTS Angiographic stenosis severity by 2D-QCA was 34% ± 13% diameter stenosis, and minimal lumen diameter (MLD) was 1.77 ± 0.58 mm. Fractional flow reserve values were 0.85 ± 0.10. Correlation coefficients between FFR and MLD or minimal lumen area (MLA) were highly significant for both 2D- and 3D-QCA (all P < .001), but higher R(2) values were observed for 3D-QCA measurements. Although significant, correlation coefficients between OCT and FFR data were weak (R(2) = 0.28, P = .001 for MLD and R(2) = 0.23, P = .003 for MLA). Correlation coefficients with FFR were significantly higher for 3D-QCA than for OCT (P values for MLD and MLA = .043 and .042, respectively). Nonobstructive stenoses with MLD >1.53 mm or MLA >2.43 mm(2) are unlikely to be hemodynamically significant. CONCLUSIONS In nonobstructive coronary stenoses, anatomical parameters derived from 3D-QCA can best identify lesions with preserved FFR values.

The Age, Creatinine, and Ejection Fraction Score to Risk Stratify Patients Who Underwent Percutaneous Coronary Intervention of Coronary Chronic Total Occlusion

Age, creatinine, and ejection fraction (ACEF) score predict clinical outcomes in patients who underwent elective percutaneous coronary intervention (PCI) of nonocclusive coronary stenoses. We aimed at assessing the prognostic value of the ACEF score in patients who underwent successful PCI of chronic total occlusion (CTO). ACEF score was calculated in 587 patients treated with PCI of CTO: successful in 433 (74%; success group) and failed in 154 patients (26%; failure group). Patients were divided in ACEF tertiles: first <0.950, second from 0.950 to 1.207, and third ACEF tertile >1.207. Major adverse cardiac events (MACE = overall death + nonfatal myocardial infarction + clinically driven target vessel revascularization) were assessed in 558 patients (95%) up to 24 months (8 to 24 months). In success group, higher MACE rate was significantly associated with increasing ACEF tertile (first = 7%, second = 13%, third ACEF = 18%, p = 0.02). MACE-free survival was significantly decreased with increasing ACEF tertile (log-rank 5.58, p = 0.018). In the failure group, lower MACE rate was significantly associated with increasing ACEF tertile (p = 0.041). This was mainly driven by significant decreasing rate of target vessel revascularization along the tertiles (first = 34%, second = 19%, third ACEF = 10%, p = 0.007). Compared with success group, in failure group, MACE rate was significantly higher in the first tertile (p <0.001) and similar in the third tertile (p = 0.59). In conclusion, ACEF score represents a simple tool in the prognostication of patients successfully treated with PCI of CTO and identifies those patients who would not derive any significant clinical harm despite failed percutaneous revascularization of the CTO.