Year : 2013 | Volume
: 1 | Issue : 1 | Page : 3--6
Dwarka Heart Institue, Delhi, India
A 16, Sector 51, Noida, Uttar Pradesh
Coronary angiography underestimates or overestimates lesion severity, but still remains the cornerstone in the decision making for revascularization for an overwhelming majority of interventional cardiologists. Guidelines recommend and endorse non invasive functional evaluation ought to precede revascularization. In real world practice, this is adopted in less than 50% of patients who go on to have some form of revascularization. Fractional flow reserve (FFR) is the ratio of maximal blood flow in a stenotic coronary relative to maximal flow in the same vessel, were it normal. Being independent of changes in heart rate, BP or prior infarction; and take into account the contribution of collateral blood flow. It is a majorly specific index with a reasonably high sensitivity (88%), specificity (100%), positive predictive value (100%), and overall accuracy (93%). Whilst FFR provides objective determination of ischemia and helps select appropriate candidates for revascularization (for both CABG and PCI) in to cath lab itself before intervention, whereas intravascular ultrasound/optical coherence tomography guidance in PCI can secure the procedure by optimizing stent expansion. Functional angioplasty simply is incorporating both intravascular ultrasound and FFR into our daily Intervention practices.
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Tewari R. Functional Angioplasty.Heart India 2013;1:3-6
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Tewari R. Functional Angioplasty. Heart India [serial online] 2013 [cited 2020 Aug 5 ];1:3-6
Available from: http://www.heartindia.net/text.asp?2013/1/1/3/113601
Coronary angiography underestimates or overestimates lesion severity, but still remains the cornerstone in the decision making for revascularization for an overwhelming majority of interventional cardiologists. Inducible ischemia during the functional testing has prognostic significance in determining when and whether to intervene.  In real world practice, this is adopted in less than 50% of patients who go on to have some form of revascularization.  Guidelines recommend and endorse non invasive functional evaluation ought to precede revascularization.  Twenty years ago, Topol et al.  reported that only 29% patients had undergone exercise testing prior to stenting. Even now, less than 45% patients have any form of preceding stress test.  Accurate Indian data on this is not available, but certainly would be much below these Figures.
Further, traditional understanding makes us endorse bypassing all lesions more than 50% stenosis. We as care providers proudly feel, we have given the benefit of "complete revascularization" to our patient and ensured better outcomes. By passing functionally insignificant proximal stenosis has now been rendered debatable with poorer graft patency rates. 
Use of objective ischemia based percutaneous coronary intervention (PCI) improves the functional status and the clinical outcomes. [6 8] Non invasive functional evaluation suffers from poor spatial resolution and low sensitivity [9 10] so revascularization should be guided by objective ischemia.
Revascularization in coronary artery diseases (CAD) is thought to be life saving  while in contrast, COURAGE, and BARI- 2D trials failed to demonstrate any benefit of stenting over optimal medical therapy in preventing death, non fatal MI, unplanned revascularization. , However, stable CAD patients having poor exercise capacity or large ischemia burden do benefit from revascularization. A large SPECT study showed benefits of revascularization were confined to those patients who have >10% ischemic burden. 
A recent study in JACC by Kim et al showed the benefits of ischemia guided PCI in multivessel CAD. Major adverse cardiac events (MACE) was significantly lower in ischemia guided PCI over non ischemia guided, largely driven by lower repeat revascularization (9.9% vs. 22.8%, hazard ratio 0.66, 95% CI 0.49 0.90, P= 0.009).
Fractional Flow Reserve - Not A New Concept, We All Know, but are Reluctant to Use as Guide
Coronary pressure measurement has been around for more than 20 years now. FFR is the ratio of maximal blood flow in a stenotic coronary relative to maximal flow in the same vessel, were it normal. Being independent of changes in heart rate, BP or prior infarction; and take into account the contribution of collateral blood flow. It is a majorly specific index with a reasonably high sensitivity (88%), specificity (100%), positive predictive value (100%), and overall accuracy (93%).
Values> 0.80 are associated with negative ischemic results with predictive accuracy of 95%. The validation of these lesion specific values has been made in numerous clinical situations  and holds true in estimating different lesions in the same vessel by pullback technique.
FFR >0.80, Stents not Needed, <0.80 Stents Justified
A total of 5 year results of the DEFER study  showed similar event free survival in deferred versus PCI group(80% vs. 73%, P = 0.5) while death and MI were 3.3% in the deferral group versus 7.9% in PCI group, (P = 0.21). This implies an annual risk of cardiac death or MI in FFR negative patients is < 1% per year and was not decreased by stenting. One could safely defer revascularization in such patients for up to 5 years.
The two year clinical outcomes of the FAME study showed the deferred group to have a 0.2% incidence of MI and 3.2% need for a repeat revascularization. 
Five years follow up of functionally insignificant lesions left on optimal medical therapy(even those with a proximal LAD) showed 5year survival of 92.9% in the medical group versus 89.6% in the re vascularized group (P = 0.74).
Stent implantation in patients with functionally insignificant disease implies greater possibility of stent thrombosis and restenotic disease- A risk that does not seem worth taking when we know that left alone on medical therapy the overall risk was very low!! Even DES usage does not alter this scenario of detrimental risk in multiple lesions as in single lesions. 
The FAME II trial was designed to compare the clinical outcomes, safety, and cost effectiveness of PCI guided by FFR plus optimal medical therapy versus optimal medical therapy alone in stable CAD.  Preliminary results showed 7.6 times greater risk of hospital readmission with revascularization for the optimal medical therapy alone group and 11.2 times greater need for urgent revascularization. Thus, stenting lesions with FFR < 0.8 seems fully justified.
The IRIS FFR DEFER study published a few months back in JACC interventions attempted to resolve this issue.  Sub analysis of the FAME trial showed that 2/3rd of the lesions with a diameter stenosis of > 50% were not ischemia producing! However, the scenario was totally different in for the left main where at least 20% of such lesions were ischemia producing. Angio FFR mismatch was defined as angiographic diameter stenosis >50% and FFR> 0.80, whereas "reverse mismatch" was defined as angiographic diameter stenosis <50% and FFR< 0.80. QCA, intravascular ultrasound, and FFR were performed and it was shown that visual functional mismatch was as high as 40%. The highlights the visual functional mismatch.
Patient's age affected the physiologic effect of a stenosis. Older patients have higher FFR than younger counterparts. Aging related loss of functional myocytes or the attenuation of vasodilatory response to adenosine could account for this. ,
Lesion location influences functional severity. Isolated left main lesions frequently show reverse mismatch. The area of supply of left main being much greater renders even a modest stenosis to assume notable functional significance.
In simpler words, this means one should consider doing FFR for even the visually innocuous lesions in left main disease.
Plaque rupture may influence the functional significance of a stenosis.  The impact of innocent plaque rupture on the functional significance is improperly understood. Theoretically, a complex lesion with irregular lumen would provide greater flow resistance and energy losses; thus, resulting in more pressure drop and reduction in FFR.
So, we now know that not just lumen size but also plaque shape, length, surface roughness or plaque rupture may be associated with changes in FFR. Thrombotic material superimposed on a ruptured plaque site may increase roughness of vessel surface and subsequently increase flow resistance; thus, adding to its functional significance.
Intravascular Ultrasound: The Interventionists' Friend!!
Do an intravascular ultrasound if you want to intervene: An FFR if you don't!! The 360 degree tomographic saggital scan of the vessel has enriched our understanding of not only atherosclerosis, but also of angioplasty. However again we know it provides anatomical information and not physiological. Attempts to integrate target lesion anatomy physiology have also been made.
The conventional teaching of stenting all lesions that reveal an intravascular ultrasound minimal lumen area (MLA) < 4 mm2 needs to be requisitioned. Can intravascular ultrasound MLA adequately predict functional significance and does it truly correspond to ischemic threshold? A 50% diameter stenosis roughly equals a 75% area stenosis and has been held significant. An MLA of 4 mm2 is equal approximately 24% diameter stenosis for a 3mm vessel and roughly equals 43% stenosis for a 4mm vessel. Other than the diameter of the stenotic vessel, we know that flow is influenced by lesion length, plaque burden, vessel size, lesion morphology, plaque characteristics, blood viscosity, collateral circulatory flow, and subtended perfusion bed.  Not all of these are as easily measurable as MLA and the summation of all these aspects would determine hemodynamic severity. It would thus be simplistic to think of MLA as being enough as a standalone criterion.
An interesting work appeared in the circulation interventions last year where intravascular ultrasound criteria were validated with FFR. Multivariate analysis showed that MLA (beta= 0.02, P= 0.032), plaque burden (beta = −0.002, P = 0.001), lesion length with a lumen area <3 mm (beta = −0.035, P = 0.001) and LAD location (beta = −0.035, =0.001) were independent predictors of FFR< 0.80. Using the ROC analysis, Kang et al proposed new intravascular ultrasound MLA criteria for predicting FFR< 0.80 was 2.4 mm2 (which was much lower than the currently held standard).
The shows that FFR values if lesions with MLA< 4 mm2 were widely scattered and 66% had MLA< 4mm, but FFR flow reserve>0.8. Using the 2.4mm MLA criterion, only 30% lesions had a MLA< 2.4, but FFR> 0.80.
So, it shows that whatever anatomical cutoff we use, MLA alone does not seem to be a sufficient standalone criterion.
Then What's the Role of Intravascular Ultrasound in Intervention?
Intravascular ultrasound has a key role in stent optimization and influences long term outcomes. In a study intravascular ultrasound MLA and stent length appeared to be the only predictors of restenosis.  Moreover, intravascular ultrasound guided DES implantation was found to significantly reduce rates of subacute stent thrombosis and cumulative stent thrombosis at 12 months.  Possible mechanisms were unclear, but as intravascular ultrasound post stenting would identify factors such as stent under expansion, malposition, inflow/outflow disease, edge dissections and thrombosis, it can be assumed that this is the manner in which intravascular ultrasound helps.
Intravascular ultrasound guidance has shown to improve long term mortality, again possibly by lowering the risk of stent thrombosis in high risk PCI including left main and bifurcation disease, , which again means that intravascular ultrasound is a very important tool and has a definite place in the armamentarium of the Interventionist.
What About Optical Coherence Tomography then?
The CLI OPCI study  published in Euro Interventions showed that optical coherence tomography group had a lower risk of cardiac death, MI or repeat revascularization. Where optical coherence tomography scores clearly over intravascular ultrasound is the spatial y structures. Resolution and enabling are much better appreciation of lumen contour, struts, and nearby structures and hence superior stent optimization.
Incorporate them both into your Practice: That's Functional Angioplasty
Functional angioplasty simply is incorporating both intravascular ultrasound and FFR into our daily Intervention practices. These are complementary and not competitive modalities. Whilst FFR provides objective determination of ischemia and helps select appropriate candidates for revascularization (for both CABG and PCI). Intravascular ultrasound/optical coherence tomography guidance in PCI can secure the procedure- pre intervention and it helps assess anatomical and post intervention helps optimize stent. This is the future of an angioplasty!!!
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