FFR & IVUS PRIOR TO REVASCULARISATION Journal review Dr.Sony Manuel M Senior Resident MCH Kozhikode

Need for Functional studies ? CAG.. limited value in defining the functional significance of a coronary stenosis ….. most imp factor related to outcome is the presence and extent of inducible ischemia. Limitations of CAG …. Intermediate lesion (40-70%) significance cannot be accurately determined Won’t provide intraluminal detail ; vessel wall details ; diffuse disease, angiographic artifacts of contrast streaming, image foreshortening and calcification often complicates the interpretation ; Bifurcation or ostial lesion locations may be obscured by overlapping branch segments. TMT,SPECT indicate ischemia in patients with MVD but fail to distinguish the specific ischemic territories and responsible stenoses.

FFR.. Developed by Pijls et al gold standard for invasive assessment of physiologic stenosis significance. ratio of the coronary pressure distal to the stenosis to aortic pressure as the normal perfusion pressure (distal coronary pressure/aortic pressure) when the microvascular resistance was minimal and assumed to be constant (ie at maximal hyperemia). FFR model assumes that under maximum arterial vasodilation,the resistance of the myocardium is minimal and constant across different myocardial vascular beds and thus blood flow to the myocardium is proportional to the driving pressure (myocardial perfusion pressure). Normal value of FFR : 1 FFR <0.75 …. inducible myocardial ischemia [ 88% sensitivity, 100% specificity, 100% positive predictive value and overall accuracy 93%] Pijls et al. nejm 1996

In this example….During maximal hyperemia (at the right side of the pressure tracing), the hyperemic distal pressure decreased to 58 mm Hg with aortic pressure of 112 mm Hg for an FFR of 0.52 (58/112). Maximal blood flow to the myocardium of the anterior wall of this patient is decreased to 52% of expected normal flow.

FFR [Kern MJ. Circulation 2000] Ischemia detection : <0.75 Defer angioplasty : >0.80 End point of angioplasty/stenting : >0.90 DEFER study: [Pijls et al.. JACC 2007] Five-year outcome after deferral of PCI of an intermediate coronary stenosis based on FFR 0.75 is excellent; The risk of cardiac death or MI related to this stenosis is 1%/ yr and not decreased by stenting. Prospective, randomized study … 1997,1998 … ‘PCI with BMS’ Patients with stable chest pain and a functionally nonsignificant coronary stenosis included ……to investigate if PCI of such stenosis is justified.

Clinical follow-up at hospital discharge and after 1, 3, 6, 12, 24, and 60 months; The primary end point was freedom from adverse cardiac events after 2 years of follow-up. 5-year follow-up …. secondary end point.

FFR Vs Angiography in Multivessel Evaluation [ ] The primary end point was the rate of death, nonfatal MI and repeat revascularization at 1 year

Baseline characteristics & angio features were not signif different in both groups

Angiographic multivessel CAD : stenoses >50% in at least 2 of the 3 coronaries ; subdivided based on visual angio severity into 50-70%, 71-90% and % stenosis. FFR guidance group (n=509): if the FFR was >0.80  functionally nonsignificant and no stent was placed. The definition of functional 0-, 1-, 2-, or 3-vessel disease was made on the basis of the number of main arteries with an FFR >0.80. In 50-70% group…..65% were not functionally significant by the FFR. In 71-90% group, 20% had FFR value above the ischemic threshold. So in MVD, one cannot rely on the angiogram to identify ischemia-producing lesions when assessing stenoses between 50-90%. Only in the angiographic stenosis category>90%, visual assessment corresponds well to a lesion’s capability of inducing myocardial ischemia because 96% of such lesions are functionally significant by the FFR

FAME study :

FAME study concludes ….. Routine FFR in addition to angiography improves outcomes of PCI at 1 year. In MVD, CAG is an inappropriate tool to identify ischemia-producing stenoses as detected by the FFR. This discrepancy between angiographic and functional stenosis severity is not only present in the 50-70% ; but also in the % stenosis range. Tonino et al. JACC 2010

FAME 2 yr follow up : Pijls et al.. JACC 2010 The 2-year rates of mortality or MI were 12.9% in the angiography- guided group and 8.4% in the FFR-guided group (p = 0.02). Rates of PCI or CABG were 12.7% and 10.6% respectively(p = 0.30). Combined rates of death, nonfatal MI and revascularization were 22.4% and 17.9% respectively (p 0.08). For lesions deferred on the basis of FFR>0.80, the rate of MI was 0.2 % and the rate of revascularization was 3.2 % after 2 years.

FFR in Multivessel Disease For Accurate lesion selection (MIBI SPECT often fails to correctly indicate all ischemic areas in 90% of patients. In 35% of such patients, no perfusion defect was present, possibly because of balanced ischemia ; In case of several stenosis in the same vessel, an abnormal SPECT wont pinpoint the most stenotic lesion)

FFR in left main & ostial lesions : The use of FFR in an LMCA stenosis has been examined in 54 patients. In those 30 patients with an FFR 0.75, medical therapy was chosen. After a follow-up of 3 years, no differences in event-free survival rate or functional class were seen between the groups. None of the patients in the medical group experienced MI or died. Bech GJ et al. HEART 2001

Serial Stenosis and Diffuse Disease When 2 discrete stenoses are present in the same vessel, the hyperemic flow and pressure gradient through the first one will be attenuated by the presence of the second one and vice versa. One stenosis will mask the true effect of its serial counterpart by limiting the maximum hyperemia that can be achieved. This fluid, dynamic interaction between 2 serial stenoses depends on the sequence, severity and distance between the lesions, as well as on the flow rate. When the distance between 2 lesions is 6 times the vessel diameter, the stenoses generally behave independently, and the overall pressure gradient is the sum of the individual pressure losses at any given flow rate. In clinical practice, the use of the pressure pullback recording is particularly well suited for identifying the several regions of a vessel with large pressure gradients that may benefit from treatment. The stenosis with the largest gradient can be treated first and the FFR can be remeasured for the remaining stenoses to determine the need for further treatment.

Diffuse Disease and Long Lesions : The location of a focal pressure drop superimposed on the diffuse disease can be identified as an appropriate location for treatment. In some cases, the gradual decline of pressure along the vessel occurs over a very long segment, such that interventional treatment is not possible. Medical treatment (or bypass surgery) can then be elected.

FFR provide prognostic information about the patient’s long-term results. In a multicenter trial, Pijls et al [750 patients] found that FFR immediately after stent implantation was an independent variable related to all MACE. The lowest MACE rates occurred in patients with the highest FFR values. FFR normalized (0.95) in 36% of patients, a finding associated with an event rate of 5%. For patients with FFRs between 0.90 and 0.95 (32% of patients), the event rate was 6%. In the 32% of patients with FFR<0.90, event rates were 20%. was 30%.

INTRAVASCULAR ULTRASOUND : to optimise stent deployment esp in complex lesions. In PCI with BMS, IVUS guidance reduces restenosis. In PCI with DES, IVUS guidance may reduce rates of stent thrombosis with little effect on restenosis. The benefit of IVUS guidance is most imp in complex lesion subsets such as left main and bifurcation lesions [IVUS guidance may reduce mortality]. Recent studies …. IVUS accurately identifies nonischemic lesions for which PCI can be safely deferred, but cannot accurately predict hemodynamically significant lesions and should not solely be used to justify revascularization. JACC Intv 2011

IVUS measurements :

Earlier studies ….MLA <4 mm 2 correlated well with ischemia on SPECT..Nishioka et al..JACC ‘99…. correlated moderately well with an FFR <0.75 in a study of 53 intermediate lesions from 43 patients, with sensitivity 92% and specificity 56%..Brigouri et al AJC low event rates were noted in 300 patients with intermediate lesions in whom intervention was deferred for an IVUS MLA >4 mm 2 …. Abizaid AS et al. circulation IVUS-derived MLA > 2.4 mm 2 may be useful to exclude FFR <0.80, but poor specificity limits its value for physiological assessment of lesions with MLA <2.4 mm 2. Thus FFR or stress tests may be necessary to accurately identify ischemia-inducible intermediate stenoses. Kang SJ et al….Circ Card Interv 2011

limitation of a single IVUS MLA cutoff : hemodynamic effects of a lesion are not only dependent on MLA, but also on numerous other factors including lesion length, eccentricity, entrance and exit angles and forces, reference vessel dimensions and the amount of myocardium subtended by the lesion. IVUS-measured MLA is only one of many factors affecting coronary flow hemodynamics. Although IVUS-derived MLA >2.4 mm2 may be a useful criterion for excluding intermediate lesions with an FFR <0.80, a MLA <2.4 mm does not always equate with functional significance. Thus, physiological assessment such as direct FFR measurement or stress tests may be necessary for identifying the ischemia-inducible stenosis that require PCI to reduce unnecessary procedures, especially in lesions with MLA <2.4 mm2 or small-vessel disease….Kang et al. Circ interv 2011

FFR is the gold standard for intermediate lesion assessment ; If IVUS is used, then the proposed algorithm for non-left main lesions is : In left main … FFR is the preferred investig …. If IVUS is used, revascularization may be deferred in patients with left main MLA > 6.0 mm2 [not associated with ischemia and have favorable outcomes]. For an MLA <6.0 mm2, consider FFR or noninvasive stress testing before revascularization.

IVUS to guide PCI : plan interv strategy & to optimise stent deployment….. find reference lumen dimensions and lesion length for appropriate stent sizing; identification of superficial calcium by IVUS can lead to pre-stent rotational atherectomy Assess thrombus burden…. operators may alter anticoagulant therapies or consider mechanical thrombectomy. Post-stent IVUS assessment may detect complications of PCI and suboptimal stent deployment Factors associated with stent thrombosis include smaller minimal stent area (MSA), stent underexpansion, persistent edge dissections, incomplete stent apposition (ISA), and incomplete lesion coverage,geographic miss, tissue protrusion and residual thrombus. Of these IVUS findings edge dissections, stent under expansion and ISA have been the most extensively investigated.

HIGH GRADE EDGE DISSECTION : lumen area narrowing 60°, have been associated with higher rates of early stent thrombosis & so should be stented…there is no consensus on optimal mgt of low grade edge D’n STENT UNDEREXPANSION. Smaller stent areas have consistently been associated with higher rates of stent thrombosis.. In 7,484 patients undergoing PCI with BMS, early thromboses were most commonly associated with inadequate post-procedure lumen area, either alone or in combination with dissection, thrombus or prolapse…. Cheneau et al. circulation 2003 In PCI with DES … limited no: of studies ; stent underexpansion and smaller MSAs (<5.0 mm2) are associated with early and late stent thrombosis; until larger studies are performed, it seems reasonable to target optimal DES expansion defined similarly to BMS criteria (80% average reference cross-sectional area). Incomplete stent apposition : acute & late Acute ISA…. Surprisingly appears not to be associated with increased cardiac events at 1 year… Steinberg et al. jacc intv 2010

Late ISA [4 times more common with DES vs BMS] is associated with increased rates of stent thrombosis. In the initial study by Cook et al. circulation ‘07, the rate of late ISA was significantly higher in patients with DES thrombosis than in control patients without stent thrombosis (77% vs. 12%, p <0.001). However, segments with thrombosis were also associated with longer lesions, longer stents, more stents per lesion,lower stent expansion index, and more stent overlap …. making definitive conclusions about the importance of late ISA in this setting difficult. Recent meta analysis …. Conflicting data …. at present, the results are inconclusive as to the relationship between ISA and long-term adverse outcomes in DES. Regardless, most operators would strive to achieve full apposition of all stent struts after stent deployment.

In unprotected LMCA PCI, the adverse consequences related to suboptimal stent deployment are more dramatic ….. IVUS guidance may be of particular importance in this lesion subset. MAIN-COMPARE trial [largest study to date of unprotected LMCA PCI… propensity score matching analysis of 210 matched patients ] … there was a trend toward lower 3-year mortality with an IVUS-guided strategy vs angiography alone (6.0% vs. 13.6%, p =0.063). Interestingly, in the 145 matched-patient subgroup receiving DES, the 3-year incidence of mortality was significantly lower in the IVUS-guided group (4.7% vs. 16.0%, p 0.048)…. related to reduced rates of sudden cardiac death related to late stent thrombosis.

IVUS-guided PCI for bifurcation lesions. Pre-intervention assessment of plaque morphology and distribution at the side branch ostium. Currently, a single-stent strategy with provisional side branch intervention has become the favored approach for most bifurcation lesions due to reduced cardiac events. In a recent propensity-matched analysis of patients undergoing PCI of non–left main bifurcations with DES using predominantly a single-stent strategy, an IVUS guided PCI strategy (n=487) (vs angio guided ; n=487)was associated with larger post-stent lumen diameters in both the main vessel and side branch lower rates of death or MI (3.8% vs. 7.8%, p =0.03).

Pre-intervention IVUS of the side branch ostium may also be useful to predict the likelihood of side branch compromise due to plaque and/or carina shift after single-stent deployment in the main branch. Recently, in 90 bifurcation lesions, a pre-intervention MLA of >2.4 mm 2 in the side branch could accurately predict a nonischemic post- intervention FFR (> 0.80) in the side branch (predictive value of 98%) after main branch stent deployment. However, a MLA<2.4mm 2 could not accurately predict side branch compromise resulting in an ischemic FFR (predictive value of 40%). At present, IVUS guidance is advocated in bifurcation lesion PCI with DES. If the pre-intervention side branch MLA is > 2.4 mm 2, provisional side branch PCI can usually be deferred. However, if the side branch MLA is <2.4mm 2, clinical judgment and/or side branch FFR should be considered to guide provisional side branch intervention.

Angiographically silent LM disease detected by IVUS is an independent predictor of cardiac events and may serve as a marker for such events. These data extend the spectrum of LM disease severity and its relationship to cardiac prognosis in patients undergoing PCI. Ricciardi MJ AHJ 2003

IVUS-guided PCI for ISR IVUS can assist in the differentiation of restenosis related predominantly to intimal hyperplasia versus mechanical complications, such as stent fracture or stent underexpansion. An IVUS-guided high-pressure angioplasty with a noncompliant balloon is often performed when stent underexpansion is the major mechanism for restenosis to avoid deployment of a second stent, especially with DES restenosis. Balloon-alone angioplasty may also be appropriate in the presence of very focal lesions due to neointimal hyperplasia in both BMS and DES. In diffuse/proliferative ISR of either BMS or DES, a second DES is often warranted.

IVUS-guided PCI for CTO Subintimal guide wire tracking ? … ‘small case series’… IVUS imaging from the false lumen to guide re-entry of the wire into the true lumen In a small series of 31 CTO lesions (of which 22 were previous failed attempts), successful recanalization was achieved in 100% of cases using a modified retrograde IVUS-guided approach.. Rathore S et al.. Jacc intrv 2010 IVUS-guided PCI for saphenous vein graft lesions SVGs are often larger making angiographic size assessment more difficult….. Oversized stents (stent to reference ratio 1.0) result in greater rates of periprocedural myocardial necrosis and distal embolization without reducing 9-month revascularization rates. In addition,stent oversizing may result in graft perforation. So it is reasonable to use IVUS to select appropriately sized stents for SVG PCI.

Radiofrequency IVUS Addition of radio frequency backscatter signal analysis allows for improved characterization of plaque composition 1)virtual histology IVUS 2) iMAP 3) Integrated Backscatter IVUS PROSPECT trial … analysed the ability of the combination of grayscale IVUS and RF backscatter analysis to predict the site of future coronary events. In PROSPECT, 697 patients presenting with ACS were enrolled and underwent PCI of all culprit lesions followed by 3-vessel VH IVUS imaging. At 3-year follow-up, nonculprit VH-IVUS defined thin-cap fibroatheromas with a plaque burden >70% and MLA<4.0 mm2 had an 18% MACE (driven largely by revascularization). Stone et al. nejm 2011 The PROSPECT trial suggests that the addition of radio frequency backscatter analysis to grayscale IVUS might provide incremental prognostic information, but further studies are warranted to investigate this hypothesis. At present, PCI of nonsignificant lesions based on plaque composition alone is not justified.

FFR vs SPECT MPI cannot be used to make these decisions in the setting of multivessel disease. Because it relies on relative flow heterogeneity, MPI usually identifies ischemia caused by the most severe stenosis; MPI, compared with fractional flow reserve, underestimated the number of ischemic territories in 36% of patients with multivessel disease…..Melikian et al. JACC Intv. 2010

References : 1) Tonino et al ; FAME Study: Fractional Flow Reserve Versus Angiography in Multivessel Evaluation:. jacc 2010;55:2816–21 2) Pijls et al. PCI of Nonsignificant Stenosis ; jacc 2007; 49 : )Pijls et al; 2 yr follow up of the FAME study :jacc 2010 ;56 : )Melikian et al; FFR and MPI in Patients With Angiographic Multivessel CAD; jacc. Intv. 2010;3: )Kern et al; Physiological Assessment of Coronary Artery Disease in the Cardiac Catheterization Laboratory : A Scientific Statement From the AHA Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology; : Circulation 2006;114: )Pijls et al. Measurement of FFR to assess the functional severity of coronary artery stenosis ; N Engl J Med 1996;334: ) Malaiapan et al. IVUS guided management of angiographic intermediate coronary lesions long term outcome after referral to pci, cabg or medical therapy; jacc 2011;57;E1851 8) Kang et al, Validation of IVUS–Derived Parameters With FFR for Assessment of Coronary Stenosis Severity ; Circ Cardiovasc Interv. 2011;4:65-71.