Poststenting Physiology

The use of fractional flow reserve (FFR) in the assessment of intermediate coronary artery lesions to guide revascularization decisions has been well studied and has a prominent place in guideline-based therapy of stable ischemic heart disease.^1-5 While the adoption of the use of FFR in clinical practice is variable, it is almost exclusively used to guide determination of lesion severity from a physiologic approach. Although postpercutaneous coronary intervention (PCI) FFR has not been widely practiced, there is a growing body of evidence that it not only predicts lesion-related clinical outcomes but can also be used in real time to improve immediate procedural outcomes via the use of additional optimization techniques and potentially hard clinical endpoints.

RESIDUAL ISCHEMIA AFTER ANGIO-GRAPHICALLY SUCCESSFUL PCI IS FREQUENT

Procedural success in PCI has traditionally been adjudicated by the angiographic visual result. However, a functional endpoint may be important to ensure good long-term outcomes. Just as it has been shown that we cannot accurately predict which lesions are functionally significant prior to therapy, there is evidence that a significant percentage of treated vessels remain with residual ischemia after PCI.⁶ Intracoronary imaging studies, including intravascular ultrasound and optical coherence tomography (OCT), have shown evidence of inadequate stent expansion and malapposition after completion of an angiographically successful PCI.^7,8 Evaluation by myocardial perfusion imaging has shown the continued presence of ischemia in up to 36% of patients immediately after coronary intervention.⁹ In contemporary practice, when using pre- and post-PCI physiology with modern-generation stents and techniques, a surprising 21% to 36% of vessels demonstrate functional ischemia despite angiographically successful stenting.¹⁰ This disconnect between what is believed to be successful PCI intended to reduce ischemia and a significant portion of patients who leave the procedure with ischemia underscores the need for a more precise approach to PCI.

PROGNOSTIC VALUE OF POST-PCI FFR

We know from the FFR arm of the FAME study that of the patients in whom repeat revascularization was needed at 2 years, a significant majority was due to failure of the target vessel rather than a de novo lesion or an FFR-deferred lesion.¹¹ Use of FFR can detect functional ischemia after stent implantation. Lower FFR has been shown in multiple studies to portend poorer outcomes.^10,12 This observation was first described in 2002 by Pijls et al who demonstrated in a 750-patient registry that postintervention FFR was correlated with adverse events at 6 months, including death, myocardial infarction, and repeat revascularization.¹² The ability to predict outcomes based on physiology with greater accuracy than by angiography alone has subsequently been demonstrated by a substudy of the FAME 2 trial, in which the natural history of the nonischemic lesions was more accurately predicted by FFR than by angiographic result.¹³ In contemporary analyses, predictive risk models have been presented and the poststent physiology was found to be highly predictive of vessel outcomes. The incremental prognostic value of FFR in the post-PCI setting was examined by Agarwal et al, showing added prognostic value of FFR over a baseline clinical model, as well as the clinical model plus angiographic data.¹⁰ In another recent analysis by Hwang et al, the most predictive variable of target vessel failure at 2 years was the total length of stent, whereas the second most important was post-PCI FFR, with other variables studied being age, diabetes, reference vessel diameter, and poststent percentage vessel stenosis.¹⁴

OPTIMAL CUTPOINTS FOR POST-PCI FFR

Although the optimal cutpoints of FFR for predictive accuracy of future clinical events vary from study to study, the relationship has been repeatedly demonstrated.⁶ Post-PCI FFR predictive values have been looked at from the balloon angioplasty era to contemporary stenting with heterogeneous populations and ongoing evolution in stent technology.^12,15-19 Not surprisingly, the varying patient populations studied have led to different optimal cutpoints. When examining an all-comer population with current-generation stent technology, a post-PCI value of FFR ≤ 0.86 by receiver operator curve analysis was independently predictive of major adverse cardiovascular events (MACE).¹⁰ When subanalysis was performed removing patients with high-risk features such as diffuse disease, chronic kidney disease, and diabetes, the optimal cutpoint was FFR ≤ 0.91 to predict MACE. Additionally, looking at the interaction of post-PCI FFR and stent type, there was a clear prognostic value of FFR > 0.86 in both groups with bare-metal stents (BMSs) as well as drug-eluting stents (DESs). The greatest event rate was in the BMS group with an FFR ≤ 0.86 (34.8%), whereas the lowest event rate was in the DES group with an FFR > 0.86 (13.1%). Importantly, the event rate of patients with DES and an FFR ≤ 0.86 (26.6%) was higher than the event rate for patients with BMS and an FFR > 0.86 (18.3%), which underscores the concept that optimization of PCI from a functional standpoint may confer as important a prognostic value, if not more, than what we have attributed to stent type. While a numerical cutoff serves a distinct clinical role in guiding practice, the reality is that post-PCI FFR is a continuous variable and relates to outcomes as a continuous function, as shown by a large study by Johnson et al.²⁰ Ultimately, while algorithms may be proposed, clinical and angiographic judgment is also necessary when deciding how to react to a post-PCI FFR value.

USE OF POST-PCI FFR IN CONTEMPORARY PRACTICE

While the prognostic value of post-PCI FFR has been demonstrated and the ability to potentially improve coronary flow has been shown, use of FFR in the post-PCI setting remains very low. Even in cases in which FFR was used before PCI, use after PCI appears to be in 9.4% of cases, as shown in the ERIS study.²¹ The reasons for lack of FFR use in the post-PCI setting are likely multifactorial but probably relate in part to the following: lack of use of pre-PCI FFR; absence of randomized controlled trials and lack of societal guidelines; side effects from adenosine, cost, and increased procedural time; and the relative inexperience with FFR by some operators, particularly after PCI. Additionally, operators may not know what to do with a suboptimal FFR result with a successful angiographic result or may be unwilling to endure further procedure time and effort to attempt to functionally optimize the PCI. Minimal post-PCI functional testing is underscored in the ERIS study, in which in patients with suboptimal post-PCI FFR, no further steps were taken in the vast majority (89%) of cases.²² Hopefully, as further randomized trials emerge, such as TARGET FFR and FFR-REACT, there will be increased adoption of physiology to improve patient outcomes.^23,24 The feasibility of functionally optimized coronary intervention, defined as using FFR before and after intervention to further treat residual ischemia in coronary stenosis ranging from 50% to 99%, was recently tested in a prospective manner and showed a very encouraging 92% strategy success rate.²⁵

MECHANISMS OF SUBOPTIMAL PCI

In the presence of a satisfactory angiographic result, there are many reasons why FFR may remain < 1.0 or even, frankly, in the ischemic range (FFR < 0.8). One common cause is diffuse atherosclerotic disease that may be underappreciated angiographically. It has been shown that vessel segments that appear angiographically normal may have plaque burden seen histologically.²⁶ The presence of diffuse disease or multiple tandem lesions may not appear angiographically significant but cumulatively may produce an ischemic FFR by the mid to distal vessel.^10,22,27 A second common cause is stent-related issues, particularly edge dissections and/or stent undersizing and underexpansion. Purely sizing by angiography alone may underestimate vessel size due to the presence of diffuse plaque, and a stented lesion may appear to be well treated when in fact by intravascular imaging, underexpansion may be evident.⁶ Edge dissection severity can also be assessed by FFR and in certain cases may aid in decision-making about adding additional stents or leaving the vessel untreated.²⁸ Additionally, in a post-PCI vessel, coronary vasoconstriction must always be considered and intracoronary nitroglycerin or other vasodilators should be given prior to performing post-PCI FFR. Finally, operators should also be aware of the accordion effect, also referred to as “wire bias,” in which the wire itself may create pseudolesions by straightening out tortuous segments.^29,30

UTILIZING POST-PCI FFR TO OPTIMIZE PCI RESULTS

Further optimization steps can decrease the presence of residual ischemia after PCI. Among the notable mechanisms of residual ischemia, diffuse disease may be more challenging to further optimize in the cath lab, although the knowledge of its presence may assist the treating physician in downstream medical management decisions. On the other hand, edge dissections, underexpanded stents, unappreciated tandem lesions, vasospasm, and some other mechanisms can be diagnosed and treated. In the aforementioned study in which 21% of angiographically successful PCIs showed persistent ischemia by FFR, further intervention showed average improvement of FFR from 0.78 to 0.87.¹⁰ These additional interventions reduced persistent ischemia from 21% to 9% of all post-PCI vessels. In another recent study of 35 patients by Wolfrum et al, 60% of patients had what was deemed to be a suboptimal post-PCI FFR of < 0.90.³¹ Greater than 60% of these cases had suboptimal stent results as determined by OCT, leading to further optimization and an increase in FFR from 0.80 to 0.88, while the remaining patients were believed to have diffuse disease as the cause of a suboptimal FFR. To illustrate the point that careful attention should be given to physiology in longer segments of disease undergoing PCI, a study by Barnauskas et al looked at patients undergoing an average of > 50 mm of stent placement. Surprisingly, 72% of such procedures resulted in an unsatisfactory PCI result, being defined as an FFR < 0.90, with 11% being in the frankly ischemic range of FFR < 0.80.²⁹

NONHYPEREMIC PRESSURE RATIOS

Nonhyperemic pressure ratios (NHPRs) have gained significant traction in contemporary coronary physiology because they are measured in the absence of adenosine infusion with the attendant savings of time, cost, and side effects to the patient. Instantaneous wave-free ratio (iFR)³² was compared to FFR and shown to be just as effective in predicting clinical outcomes.^32,33 Subsequently, diastolic hyperemia-free ratio,³⁴ resting full-cycle ratio,³⁵ and the distal coronary/aortic pressure ratio (Pd/Pa) have shown similar correlation with iFR.^36,37

In the post-PCI setting, several studies have looked at the predictive values of NHPRs in comparison with FFR as a corollary to the pre-PCI diagnostic setting. In one study evaluating the correlation between post-PCI FFR, iFR, and Pd/Pa, the degree of ischemic resolution after PCI as detected by iFR was similar to that of FFR (ΔiFR 0.20 ± 0.21 vs ΔFFR 0.22 ± 0.15; P = .25).³⁸ Additionally, the pullback function in iFR to assess changes in coronary flow through tandem lesions has been looked at in the post-PCI setting, suggesting a high predictive accuracy of iFR in comparison to FFR.³⁹ The prospective, observational DEFINE PCI study used iFR pullback post-PCI in 562 vessels in which iFR was used pre-PCI to stratify need for revascularization. Twenty-four percent of patients remained with residual low iFR (iFR < 0.90), of which 18.4% were believed to have diffuse disease, whereas the remaining 81.6% had a focal issue either within the stent (38.4%) or an additional lesion location (61.6%).⁴⁰

Pd/Pa is a simple ratio of full-cycle resting distal coronary pressure to aortic pressure. It is universally available on all pressure wire systems and therefore has significant appeal for widespread use. Post-PCI Pd/Pa was measured in a large study also looking at post-PCI FFR and demonstrated a significant correlation between the two indices in predicting MACE.⁴¹ A post-PCI cutoff of ≤ 0.86 had the best predictive accuracy of MACE for FFR (17% vs 23%; log-rank P = .02), whereas a post-PCI cutoff of ≤ 0.96 was the best predictor of MACE for Pd/Pa (15% vs 24%; log-rank P = .0006). Moreover, it was found that Pd/Pa was an independent predictor of MACE with incremental prognostic value when added to a clinical, angiographic, and FFR predictive model. The investigators recommended that post-PCI Pd/Pa could be measured and PCI could be considered successfully completed with a Pd/Pa > 0.96. With a Pd/Pa ≤ 0.96, FFR should then be measured and if the FFR is ≤ 0.86, further optimization should be performed, including FFR pullback for localizing lesions, intravascular imaging, and potentially additional postdilation or other intervention.⁴¹ With with the development of pressure wires that are easily handled and that can be used as workhorse wires, the barrier for use of physiology can more easily be overcome because NHPRs can augment a clinician’s procedural success and patient outcomes without significantly increasing procedure time, cost, and patient side effects.

CONCLUSION

From the perspective of population health, medicine heads more toward guidelines and algorithm-based treatment. Interventional cardiology is no exception. We have learned that there are imprecisions in our use of angiography in determining severity and thereby prognosis of coronary lesions and that the use of physiology is much more relevant in improving clinical outcomes than angiographic anatomy alone. The use of physiology to determine the need for coronary intervention, as well as to optimize the outcome of coronary intervention, is a step toward the three Ps of coronary artery disease therapy (“personalization,” “precision,” and, ultimately, “perfection”). Functional testing after intervention should be at the forefront of guideline-based recommendations as we gather more evidence in its use, so that we can continue to refine our treatment of coronary artery disease.

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