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The Take Home: EuroPCR
Some of the hottest topics in interventional cardiology, from physiologic assessment to renal denervation, were addressed at EuroPCR, held in Paris from May 22 to May 25. Cardiology Today’s Intervention discussed some of the presentations with numerous experts, including William E. Boden, MD, FACC, FAHA, from Boston University School of Medicine, Harvard Medical School and VA New England Health Care System; Bernard De Bruyne, MD, PhD, from Cardiovascular Center Aalst, Onze-Lieve-Vrouw Clinic; Kirk N. Garratt, MD, MSc, MSCAI, from Christiana Care Health System; Cardiology Today’s Intervention Associate Medical Editor Roxana Mehran, MD, MSCAI, FACC, FAHA, FESC, from Icahn School of Medicine at Mount Sinai and the Cardiovascular Research Foundation; Cardiology Today’s Intervention Editorial Board Member David J. Moliterno, MD, FACC, from the University of Kentucky; and John P. Reilly, MD, FACC, from Ochsner Health System.
SPYRAL HTN-ON MED and RADIANCE-HTN SOLO
Reilly: Two sham-controlled trials demonstrating the efficacy of renal denervation may have rekindled hope for the technology as a treatment for hypertension. In the SPYRAL HTN-ON MED trial of 80 patients taking one to three antihypertensive medications, patients assigned renal denervation with the Symplicity Spyral multielectrode renal denervation catheter (Medtronic) and the Symplicity G3 renal denervation RF generator (Medtronic) had greater reductions in 24-hour ambulatory and office systolic and diastolic BP at 6 months compared with those assigned a sham procedure (P < .05 for all). In the RADIANCE HTN-SOLO trial of patients not on antihypertensive medications, those assigned to renal nerve ablation with an endovascular ultrasound renal denervation system (Paradise, ReCor) had a greater reduction in daytime ambulatory BP at 2 months than those assigned a sham procedure (P < .0001 in intention-to-treat and per-protocol analyses).
It’s important to remember that a number of studies before these suggested that renal denervation would be a beneficial therapy for hypertension; the failed SYMPLICITY HTN-3 trial which garnered a lot of attention was the outlier.
Renal denervation will become one option to treat hypertension. We don’t yet know which patients are most likely to benefit. We need more analysis of risks and benefits, and of where it is cost-effective. The treatment effect on BP seen in these studies is similar to a patient losing 20 pounds.
The RADIANCE HTN-SOLO trial corroborated the findings of SPYRAL HTN-OFF MED, which was published in August 2017. Both showed that renal denervation was better than being on no medications. When the TRIO trial of the ReCor device in patients with hypertension resistant to medications is published, and we get more data from SPYRAL HTN-ON MED, those will be important next steps in learning how to treat patients with truly resistant hypertension. We also need to do a cost analysis. Although renal denervation is a one-time procedure, which is very attractive, and may have a long-term benefit, hypertension drugs are relatively cheap, so the cost analysis will be important.
These data are very exciting and deserve more attention than they are getting, given that hypertension is an underlying cause of heart disease.
ORBITA PHYSIOLOGY SUBSTUDY
Boden: These findings are similar to the old saying that “beauty is in the eye of the beholder.” The finding that the worse the fractional flow reserve/instantaneous wave-free ratio values, the more severe the ischemia, and thus one would predict significantly improved regional wall stress by echo (shown also in the original Lancet paper) is reinforced in this new presentation and paper.
In 196 patients who underwent FFR or iFR before their PCI or sham procedure, PCI improved stress echocardiography score compared with placebo (1.07 segment units; 95% CI, 0.7-1.44). The placebo-controlled effect of PCI on stress echocardiography score increased progressively with decreasing FFR (P for interaction < .00001) and decreasing iFR (P for interaction < .00001). There was no significant improvement in angina frequency score among patients who received PCI compared with those who received placebo, but there was an increase in patient-reported freedom from angina in patients who underwent PCI compared with placebo (49.5% vs. 31.5%; OR = 2.47; 95% CI, 1.3-4.72).
However, one would predict improved angina and exercise tolerance in these patients compared with those with less severe ischemia (based on iFR/FFR criteria), and yet there was no relationship with the FFR/iFR results predicting a symptomatic improvement — so there is an apparent disconnect between the physiologic improvement in regional wall motion score and exercise capacity. This tells me that the PCI was technically successful in improving regional echo wall motion but not exercise treadmill time, nor most of the Seattle Angina Questionnaire quality of life domains — except for the “freedom from angina” domain. That is, the angina frequency, physical limitation, and overall quality of life Seattle Angina Questionnaire domains were no different for the PCI group compared with the sham group. Overall, I would conclude that these are somewhat discordant results and “mixed signals.” Nor do these findings really change the overall ORBITA findings.
However, I predict that many interventional cardiologists will seize upon the “freedom from angina” domain with PCI and will now argue that ORBITA is actually a “positive trial for PCI,” and many may simply choose to ignore the other quality of life domains, including no change in exercise increment, and will attempt to argue that these findings negate the original Lancet findings — though I do not agree with this interpretation.
Here is another issue: If PCI was technically successful in normalizing the post-PCI FFR and iFR values and also improved regional echo wall stress scores, why were so many patients (47%) still assessed by their blinded physicians as having persistent Canadian Cardiovascular Society Class 2-3 angina post-PCI, and why did 50% of the PCI-treated patients not have complete “freedom from angina,” as noted in Figure 4 of the Circulation publication, post-PCI at 6 weeks? There seems to be a disconnect between symptom relief and physiologic parameters (incremental improvement in exercise duration) and all but one Seattle Angina Questionnaire domain. So, there are still more questions than answers.
It is also notable that the FFR/iFR values post-stenting were good to very good (0.9 and 0.95 respectively, although not perfect), and the majority of patients (95% to 98%) had values that were in the normal range after PCI. This argues against significant residual ischemia due to poor technical result or diffuse untreated epicardial CAD.
The only way I could try to rationalize these findings (aside from statistical concerns or small sample size) is by citing the “ischemic cascade.” But, the first changes with ischemia are regional wall motion and the last change temporally is chest pain/angina, which is the last parameter temporally that manifests physiologic improvement. FFR/iFR parameters are based on coronary flow, and thus are most sensitive at detecting the early signs of ischemia based on reduced perfusion. Other factors such as collateral recruitment or microvascular augmentation might be able to compensate for the decrease in flow to maintain enough myocardial supply to prevent the last stage of ischemia (chest pain). Changes in regional wall motion abnormalities are more sensitive and occur at an earlier stage of ischemia compared with angina.
Another plausible explanation for the disconnect between improved regional wall stress and freedom from angina without any notable change in exercise parameters is that the patients’ angina and exercise limitation was not predominantly due to the epicardial coronary stenotic lesions to begin with, and could potentially be explained by other mechanisms for angina that are separate from severe epicardial disease, such as microvascular angina and ischemia — which can co-exist in the same patient. Therefore, by stenting a high-grade 90%+ segmental coronary stenosis, they “fixed the ischemia” as manifested by both the FFR/iFR and the echo improvement, but not the symptoms. In these patients, it is plausible that the predominant driver of angina is microvascular disease in the culprit coronary artery or the other coronaries that were not evaluated; one would typically use an adenosine infusion to assess coronary flow reserve. In that situation, iFR/FFR is not going to be valuable tool to help predict those that will have improvement in angina or exercise. One could suggest that any future study that is going to analyze the effect of medical therapy or PCI on angina as the primary outcome should also involve parameters that carefully assess the microvasculature at baseline and follow up, such as global coronary flow reserve, hyperemic microvascular resistance or index of microcirculatory resistance.
The takeaway is that not all angina is due to obstructions or stenosis of the epicardial coronary arteries and that angina and ischemia can also be caused by microvascular disease and endothelial dysfunction. Many critics bashed the ORBITA trial because they disbelieved that stenting a flow-limiting coronary stenosis would not be associated with improvements in angina and improved exercise duration, but these new findings do show some evidence for the “freedom from angina” Seattle Angina Questionnaire domain — yet angina frequency, physical limitation, Seattle Angina Questionnaire quality of life and the EQ-5D measures were unrevealing of a clear PCI benefit. And, why do only 50% of successfully stented patients not have complete angina relief post-PCI at 6 weeks when one would expect the maximal benefit to be discernible?
Obviously, we await the outcomes of the large ISCHEMIA trial, where we will have an opportunity to examine clinical outcomes and detailed quality of life in over 5,170 patients with stable CAD and moderate-to-severe baseline ischemia where half the patients will get revascularization, mostly with PCI, plus optimal medical therapy and the other half will get optimal medical therapy alone, though this is an unblinded trial. But, if ischemia is the major driver of events, we will likely be able to test this hypothesis fully during long-term follow-up
But, when the dust settles, I do believe the present analysis tells us that PCI, as it would be expected to, improves regional wall motion and at least the one Seattle Angina Questionnaire domain of “freedom from angina” — which it also should if you relieve a 90%+ segmental stenosis. However, not all angina domains were improved nor was exercise, so at the present time, there are still more questions than answers. That said, hopefully, the discourse and dialogue post-ORBITA will now proceed in a more civil and less contentious fashion.
Garratt: ORBITA was the first sham-controlled PCI trial and was appropriately considered a better type of study than the PCI studies that had come before. With the physiologic data being released, we are able to gain further insight.
When the original ORBITA data were released, it was reported that that the degree of ischemia measured with dobutamine stress echocardiography was improved in patients with PCI more than with medications alone. This was noteworthy because dobutamine stress echo is a relatively reliable measure of ischemia. In a statement from the Society for Cardiovascular Angiography and Interventions, I noted that this measure may have greater relevance to patient care than exercise time, since it may be less influenced by factors that could impact a patient’s tolerance to exercise. There are many reasons why one would not exercise to one’s true maximum tolerance, that is, the degree that is determined by ischemic burden, when on an exercise treadmill. A dobutamine stress echo test eliminates all those factors and is in many ways a better measure of ischemic burden. So, we knew before the physiology data were released that this measure of ischemic limitation was improved more with PCI than medications alone.
The release of the physiology data now confirms that impression. We can now see how patients fared with angioplasty as a function of their iFR or FFR values. Happily, the improvement on dobutamine stress echo was greatest among those who had the lowest FFR values. This tells us that patients who have the most ischemia are likely to get the most ischemic relief from PCI. This makes sense.
What is interesting and as yet unexplained is why patients did not also seem to have the same degree of benefit in relief of anginal symptoms. We now know that even among patients with very abnormal FFR or iFR values, the relationship between PCI and angina relief is not very good, except when you consider the dichotomous variable of presence or absence of angina. PCI was much more effective than medications alone in rendering patients angina-free. However, among patients who continued to have angina, the degree of benefit after PCI didn’t correlate well with the magnitude of FFR or iFR abnormality.
What we can say is that we can be highly confident that angioplasty, when done correctly and successfully in appropriate patients, relieves ischemia, and that ischemia relief can improve function and render patients angina-free. There are still patients who will be limited by angina despite having a successful PCI experience. Perhaps microvascular disease or other problems may limit them. We still do not understand all the variables that may be at play in those patients.
The new ORBITA data confirm the value of FFR and iFR. We use those tools to identify patients who are suitable for PCI. Nothing in the ORBITA dataset convinces me that I should change my approach with respect to using those invasive tools to help identify patients who are likely to benefit.
Right now, clinical practice should remain the same. Nothing in the new analysis seems to run counter to our current clinical guidelines, which say that patients must have limiting symptoms or objective findings of ischemia and must have a reasonable trial of medical therapies without evidence of adequate improvement before they go to the cath lab. For patients who go to the cath lab, lesions of indeterminate severity should be assessed further with FFR, iFR or a similar tool to confirm that the lesions are sufficiently severe to induce ischemia. Nothing in the ORBITA study should change any of that.
A larger trial with hard endpoints such as objective measures of ischemia would be welcome. Criticisms have been levelled against the ORBITA study about its relatively small sample size and the use of exercise time as a primary endpoint. Conducting an ORBITA-like study in a larger population of patients with unimpeachable endpoints would increase confidence in findings, and that would certainly be welcome.
FAME 2
De Bruyne: The role of PCI in patients with stable coronary artery disease remains very controversial. There are a lot of positive data for PCI in patients with unstable syndromes, but in stable disease, we have very few data. The aim of the FAME 2 study, for which I was an investigator, was to compare the rates of death, MI and urgent revascularization after fractional flow reserve-guided PCI plus medical therapy vs. medical therapy alone in 1,220 patients with stable CAD.
At 5 years, death, MI or urgent revascularization occurred in 13.9% of the group who underwent FFR-guided PCI vs. 27% of the group assigned medical therapy alone (HR = 0.46; 95% CI, 0.34-0.63).
The patients who did not have at least one stenosis with FFR of 0.8 or less were not included in the randomized trial but were put in a registry and given medical therapy. Those patients did not significantly differ from the PCI group in the primary endpoint at 5 years (PCI, 13.9%; registry, 15.7%; HR = 0.88; 95% CI, 0.55-1.39).
The event rate of the patients in the registry was almost identical to that of the patients who got a stent, which means that if we target the stenosis, and we alleviate the ischemia-producing lesions by stenting with drug-eluting stents, we put the patients exactly on the event curve as if they never had ischemia. That is a very important finding.
ERIS
Mehran: Even though this was a nationwide pool of patients, it is still a small cohort and it is a registry, not a randomized study. Of large number of cases performed, approximately 1,800 patients were included in this registry. A majority of patients had physiology-guided PCI, but one-third had angiographic visual assessment only to guide PCI. The truth is that physiology studies are used in a small number of patients, even though there are great outcomes data associated with them. They are used in about 10% of cases, and in this study, their use ranged from 7% to 13%. Many cases in this study (48% overall; 45% in patients with ACS) were performed in accordance with U.S. and European guidelines, but many physicians don’t want to use physiology because they are very confident in their visual estimate and the patient’s presentation and symptomatology.
These results reflect what is going on in the real world and are thus important. We have to incorporate physiology whenever we have any small doubt. Now that FFR and iFR are available and there is increased awareness of them, there should be more physiologic assessments performed to inform our treatments. In many ways, we can curtail how we do PCI, performing it in a much more guideline-driven way if we incorporate physiology more. Angiography is two-dimensional imaging and doesn’t tell us anything about functional status of the coronary stenosis or ischemic burden. This study tells us we should incorporate physiology whenever possible.
TROFI II
Moliterno: The observations from this small study continue to support the general concepts of a resorbable stent — that the resorbable scaffolds do go away over time and leave behind similar vascular dimensions and downstream physiology compared with permanent stents.
In the 38 patients included in the final analysis, more patients treated with a bioresorbable vascular scaffold (Absorb BVS, Abbott Vascular), compared with an everolimus-eluting stent (Xience, Abbott Vascular), had vasoconstriction to acetylcholine (77.8% vs. 25%; P = .008) and vasodilation to nitroglycerin (61.1% vs. 18.8%; P = .018) in the scaffold or stent segment.
However, this study will not affect current practice as there are no attractions, yet potential distractions, to a scaffold with unpredictable and potential deleterious dismantling. For example, dual antiplatelet therapy may need to be prolonged further with such a resorbable platform until proof of long-term avoidance of scaffold thrombosis is established.
While this study was not so focused on CV health, but rather potential differences between a resorbable scaffold vs. a permanent stent, it is impressive that despite at least 3 years of presumed measures to improve CV health (eg, smoking cessation, aggressive lipid lowering, cardiac rehabilitation), that the majority of patients (> 60%) still had endothelial dysfunction (ie, paradoxical vasoconstriction to acetylcholine). In fact, that the “cage” had disappeared among most patients receiving the resorbable scaffold, such patients were able to demonstrate this paradoxical vasoconstriction in the stented segment compared with those receiving a permanent stent, and that does not seem attractive. Are we again focused on the scaffold vs. stent and not on the patient?
SYNTAX II FFR-CT SUBSTUDY
Mehran: This is a small study, but it has very important implications. The investigators tried to see if we could classify patients using noninvasive FFR into SYNTAX scores using CT-derived FFR (FFR-CT). In these patients (n = 77), lesions were able to be reclassified similar to an invasive physiologic assessment. The diagnostic accuracy of FFR-CT to detect functional significant stenosis based on iFR of 0.89 or less was reflected in an area under the receiver operating characteristics curve of 0.85 (95% CI, 0.79-0.9), a sensitivity of 95% (95% CI, 89-98), a specificity of 61% (95% CI, 48-73), a positive predictive value of 81% (95% CI, 76-86) and a negative predictive value of 87% (95% CI, 74-94).
This is a very interesting way of us to be able to assess patient’s eligibility for PCI v. CABG and classifying their lesion severity non-invasively. This could allow the heart team to be more aware and fully engaged earlier than usual in patients with multivessel disease. We may be able to accurately downgrade or upgrade patients to bypass or PCI without an invasive measurement. Larger randomized studies are needed to validate these findings, but the feasibility of this approach has been shown and it could be an important game changer.
Disclosures: Boden, Garratt and Moliterno report no relevant financial disclosures. De Bruyne reports he has received grants from Abbott and Opsens. Mehran reports she has financial ties with numerous drug and device companies. Reilly reports he has served as a site investigator for several renal denervation trials, including RADIANCE HTN-SOLO, without compensation.