Clinical Editor's Corner: Kern

Is the FAME Approach to CAD in TAVI Patients Applicable?

Morton Kern, MD, MSCAI, FACC, FAHA

Clinical Editor; Chief of Medicine, Long Beach VA Medical Center, Long Beach, California;

Associate Chief Cardiology, University of California, Irvine Medical Center, Orange, California

Morton Kern, MD, MSCAI, FACC, FAHA

Clinical Editor; Chief of Medicine, Long Beach VA Medical Center, Long Beach, California;

Associate Chief Cardiology, University of California, Irvine Medical Center, Orange, California

Coronary artery disease (CAD) is common in many of our patients undergoing transcatheter aortic valve implantation (TAVI). In randomized trials of intermediate-and high-risk patients, more than two-thirds of TAVI candidates had CAD.1,2 In practice, it is not clear that CAD will negatively affect clinical outcomes after adjustment for comorbidities.3 Additionally, percutaneous treatment of CAD before TAVI has not been associated with lower in-hospital or 1-year mortality or improved symptoms long term.4 At present, current recommendations and clinical judgement indicate that percutaneous coronary intervention (PCI) before TAVI should be limited to significant stenoses of proximal major coronary arteries, mostly the left anterior descending (LAD) coronary artery.

Why Does PCI Not Demonstrate Clinical Benefit in TAVI Patients?

Possible explanations underlying the inconclusive results of PCI for TAVI patients include the fact that the some of the treated lesions are not hemodynamically significant — a situation very similar to those found in the FAME study. FAME (fractional flow reserve [FFR]-guided vs only angiographically-guided PCI) found that among patients with angiographic 3-vessel disease, more than 75% had only 2-vessel or even 1-vessel functionally significant lesions that would benefit from stenting. While functional assessment of CAD using FFR or non-hyperemic pressure ratios [NHPR] (eg, instantaneous wave-free ratio [iFR] or relative flow reserve [RFR], etc.) have demonstrated an important beneficial impact on decision making and outcomes in CAD patients without aortic stenosis, the diagnostic accuracy of physiologic indexes in the aortic stenosis patient with a pressure-loaded left ventricle is unknown.

Aortic stenosis is associated with increased left ventricular systolic (and often diastolic) pressure, left ventricular hypertrophy, and diastolic dysfunction with impaired relaxation. Increased systolic myocardial compressive force across both systolic and diastolic periods are postulated to affect physiological indexes.5 The impact of microvascular impairment on the validity of FFR suggests that FFR, even more than NHPR-iFR, may underestimate the severity of intermediate coronary stenoses.6,7

FFR/iFR in Aortic Stenosis and TAVI

In the aortic stenosis patient, FFR/NHPR is influenced by the preexisting pressure overload before TAVI and after TAVI, in theory, the reduction of aortic outflow gradient (and resistance) with increased flow may decrease the post-TAVI FFR value (ie, higher flow, lower FFR). Wiegerinck et al8 assessed 133 coronary stenoses by FFR in 54 patients with severe aortic stenosis before and after TAVI during the same procedure. Interestingly and not as expected, no significant overall change in FFR values was found before and after TAVI (0.89±0.10 vs 0.89±0.13; P=.73). However, a different trend between the positive (FFR≤0.8) and negative (FFR>0.8) groups was found after TAVI. Positive FFR values worsened after TAVI (0.71±0.11 vs 0.66±0.14). Conversely, negative FFR values improved after TAVI (0.92±0.06 vs 0.93±0.07). Fortunately, only a small number of patients had their indications to treat the coronary stenosis changed (only 8 of 133, 6%) suggesting that after TAVI, FFR variations are minor and rarely crossed the diagnostic FFR cutoff of 0.8 to change the therapeutic approach.

Looking at the diagnostic performance of iFR and FFR in aortic stenosis patients, Scarsini et al9 assessed 179 coronary lesions with iFR and FFR measurements in 85 aortic stenosis patients and compared with a control group of 167 patients (290 lesions) with stable CAD and without aortic stenosis. The correlation between iFR and FFR was similar between aortic stenosis and CAD patients, as well as the area under the curve (AUC, a measure of concordance, 0.97 vs 0.96, P=.88). However, using the iFR threshold of 0.89, the diagnostic accuracy of iFR was significantly lower in aortic stenosis compared with CAD (76.3% vs 86.1%, P=.009). According to AUC analysis, the best iFR cut-off in predicting FFR≤0.8 was lower in aortic stenosis (0.83) compared with CAD (0.89). Using the cut-off of 0.83, the iFR accuracy increased significantly (91.3%, P=.003) while maintaining an elevated negative predictive value (95.5%). These findings suggest that in the aortic stenosis patient, the conventional iFR cut-off (0.89) had lower diagnostic agreement with FFR compared to stable CAD patients. Of note, mean iFR values remained identical before and after TAVI, irrespective of the angiographic severity of the coronary stenosis (0.89±0.12 vs 0.89±0.12, P=.66). However, individual iFR values varied widely after TAVI and the 0.89 iFR threshold was crossed by 15% of the investigated coronary lesions. Higher iFR variation was also related to a higher transaortic gradient drop after TAVI. The diagnostic accuracy of iFR in predicting a FFR≤0.8 was poor (65%) and tended to increase post TAVI. The reasons for such a variation in the aortic stenosis patient remain unknown at this time. These findings suggest that although the overall values did not change after TAVI, iFR presented significant and mostly erratic individual variations after the valve replacement. The ΔiFR was influenced by the extent of the Δtrans-aortic TAVI gradient. Therefore, caution is advised in interpreting iFR in aortic stenosis patients.

Is the FAME Study Approach to Patients With CAD Undergoing TAVI Applicable?

The FAME study10 told us that FFR-guided PCI compared to angiographic-guided PCI reduces myocardial infarction and death over 5 years in patients with multivessel CAD. Recently, Lunardi et al11 analyzed the clinical outcome of FFR-guided PCI in patients with CAD undergoing TAVI, in a manner nearly identical to that used in the FAME study. A retrospective review of 432 patients with CAD and severe aortic stenosis were divided into 2 groups: angiography-guided (122/216; 56.5%) or FFR-guided revascularization (94/216; 43.5%). Patients were followed for major cardiac and cerebral adverse events (MACCE) for 2 years. The investigators found that 78% of lesions in the FFR group were not hemodynamically significant with FFR<0.80 and these lesions were deferred from stenting at that time. Compared with the angio-guided group, the FFR-guided group showed a high event-free survival rate (92.6% vs 82.0%; P=.035). Patients with FFR-deferred lesions had better outcomes compared with patients who underwent angio-guided PCI (91.4% vs 68.1%; P=.001). From this well-done study, it appears that, as in the FAME study, FFR guidance in TAVI patients with CAD was associated with a more favorable outcome than angiographically-guided stenting (Figure 1). These results should be viewed cautiously, given the limitations of the study design (eg, observational rather than prospectively studied). To incorporate this practice going forward will require more randomized trials to validate the benefit on long-term effects of the FFR-guided approach.

Can We Differentiate the Cause (CAD vs Aortic Stenosis) of a Patient’s Symptoms When Both Are Present?

In patients with aortic stenosis without CAD, chest pain or angina-like symptoms are attributed to abnormal microvascular responses because of the associated left ventricular hypertrophy due to aortic stenosis. To this point, Ahmad et al12 asked, “What is the impact of the microcirculation on the physiologic indexes we use to assess the CAD?” This prospective study looked at 140 patients divided into 2 groups: 55 patients with severe AS and intermediate coronary stenoses treated with TAVI (group 1) and another separate cohort of 85 patients with intermediate coronary stenoses without AS (group 2). Translesional pressure measurements at rest (iFR) and during hyperemia (FFR) in both groups were made before and after TAVI (group 1) and before and after PCI in group 2. The investigators found that, after TAVI, both the microvascular resistance as well as the microvascular reserve (hyperemic/basal resistance, both measured during the wave-free period) increased, and were independent of the stenosis severity. The change in microvascular resistance post TAVI was equivalent to that produced by stenting a severe coronary lesion only if the iFR was ≤0.74. At the moment, demonstrated improvement in post-TAVI microcirculatory function recorded in this study suggests that although TAVI can impact myocardial recovery, there are limitations of FFR/iFR for CAD decisions in the aortic stenosis patient, findings contrary to the study of Lunardi et al11.

How Much Does Aortic Stenosis Affect Coronary Flow Reserve?

Coronary flow reserve or vasodilatory reserve (CFR) is the ratio of hyperemic to basal coronary flow or velocity, and impaired CFR is thought to be the mechanism of chest pain in aortic stenosis patients without CAD. Wiegerinck et al8 measured CFR in an unobstructed coronary artery in 27 aortic stenosis patients before and immediately after TAVI and in 28 control patients without aortic stenosis. Baseline flow velocity was higher and baseline microvascular resistance was lower in patients with aortic stenosis compared with controls. Although hyperemic flow velocity in patients with aortic stenosis was significantly lower compared with controls (approximately 20%, P=.04), hyperemic microvascular resistance was not significantly higher in patients with aortic stenosis compared to controls, resulting in a lower CFR in aortic stenosis patients (1.9±0.5 vs 2.7±0.7, P<.001). While the CFR is reduced in aortic stenosis before TAVI, the improved microvascular resistance and flow after TAVI account for an improved CFR, which in theory may reduce the post-TAVI FFR value, whereas a change in basal flow may alter the post-TAVI iFR in aortic stenosis patients undergoing CAD evaluations. A summary of postulated changes in physiology influencing lesion assessment after TAVI is shown in Figure 2.

The Bottom Line

How should we treat CAD in TAVI candidates until prospective data are available? Several studies support the recent work of Lunardi et al11 and demonstrate that FFR-guided revascularization is feasible and safe, and results in deferral of unnecessary stenting in a large proportion of patients, leading to a potential reduction in MACCE13. Presently, I agree with the opinion of Davies and Piek14, that the “intrinsic variability of measurement in a heterogenous group of patients with aortic stenosis means it is important to be cautious with definitive conclusions whilst the field is evolving.” The next decade of studies will likely demonstrate similar outcomes using NHPRs (eg, iFR, RFR, DPR, etc.).

At this time, I believe we should use functional (FFR/NHPR) assessment of CAD for best decisions in this often elderly and frail patient group. The FAME study demonstrated that FFR produced better outcomes over angiography alone in multivessel CAD patients and it is my belief that FFR will help make similar decisions, with similar outcomes, in the aortic stenosis patient with CAD. 

Disclosures: Dr. Morton Kern reports he is a consultant for Abiomed, Abbott Vascular, Philips Volcano, ACIST Medical, Opsens Inc., and Heartflow Inc.

  1. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med. 2016; 374: 1609-1620.
  2. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011; 364: 2187-2198.
  3. Abdel-Wahab M, Zahn R, Horack M, et al. Transcatheter aortic valve implantation in patients with and without concomitant coronary artery disease: comparison of characteristics and early outcome in the German multicenter TAVI registry. Clin Res Cardiol. 2012; 101: 973-981.
  4. Kotronias RA, Kwok CS, George S, et al. Transcatheter aortic valve implantation with or without percutaneous coronary artery revascularization strategy: a systematic review and meta-analysis. J Am Heart Assoc. 2017; 6: e005960. doi: 10.1161/JAHA.117.005960.
  5. Camuglia AC, Syed J, Garg P, et al. Invasively assessed coronary flow dynamics improve following relief of AS with transcatheter aortic valve implantation. J Am Coll Cardiol. 2014; 63: 1808-1809.
  6. Pesarini G, Scarsini R, Zivelonghi C, et al. Functional assessment of coronary artery disease in patients undergoing transcatheter aortic valve implantation: influence of pressure overload on the evaluation of lesions severity. Circ Cardiovasc Interv. 2016; 9: e004088.
  7. Scarsini R, Pesarini G, Zivelonghi C, et al. Physiologic evaluation of coronary lesions using instantaneous wave-free ratio (iFR) in patients with severe AS undergoing transcatheter aortic valve implantation. EuroIntervention. 2018; 13: 1512-1519.
  8. Wiegerinck EMA, van de Hoef TP, Rolandi C, et al. Impact of aortic valve stenosis on coronary hemodynamics and the instantaneous effect of transcatheter aortic valve implantation. Circ Cardiovasc Interv. 2015; 8: e002443. doi: 10.1161/CIRCINTERVENTIONS.114.002443.
  9. Scarsini R, Pesarini G, Zivelonghi C, et al. Physiologic evaluation of coronary lesions using instantaneous wave-free ratio (iFR) in patients with severe AS undergoing trans-catheter aortic valve implantation. EuroIntervention. 2017 Aug 29. pii: EIJ-D-17-00542. doi: 10.4244/EIJ-D-17-00542.
  10. van Nunen LX, Zimmermann FM, Tonino PA, et al. Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomized controlled trial. Lancet. 2015;386:1853-1860.
  11. Lunardi M, Scarsini R, Venturi G, et al. Physiological versus angiographic guidance for myocardial revascularization in patients undergoing transcatheter aortic valve implantation. J Am Heart Assoc. 2019; 8: e012618. doi: 10.1161/JAHA.119.012618.
  12. Ahmad Y, Vendrik J, Eftekhari A, et al. Determining the predominant lesion in patients with severe AS and coronary stenoses: a multicenter study using intracoronary pressure and flow. Circ Cardiovasc Interv. 2019; 12: e008263. doi: 10.1161/CIRCINTERVENTIONS.119.008263.
  13. Mylotte D, Wijns W. Anatomical or functional assessment of coronary artery disease in aortic stenosis: haven’t we been down this road before? J Am Heart Assoc. 2019; 8: e014367. doi: 10.1161/JAHA.119.014367.
  14. Davies JE, Piek JJ. Time for caution interpreting coronary physiology in aortic stenosis? EuroIntervention. 2018; 14: 132-134.