Gre8t Debates: Eight Current Controversies in Interventional Cardiology

Cover Story | See a patient with a non-ST elevation MI and you act—but is your invasive strategy better early or later? What about single; no, dual; no, triple antiplatelet/antithrombotic therapy—and for how long and when? What about PCI: thienopyridines and/or GPIs and/or antithrombotics and/or what? Use a circulatory support device, but which one in which patient? And what about CTCA in patients presenting with stable chest pain?

Try this, try that. But be ready for someone else to think trying that is so much better than trying this. No matter whose guidelines say what.

For eight of the hotter-under-the-collar topics of late in interventional cardiology, we looked to the most recent meetings in the United States and Europe.

An Early Invasive Strategy for NSTE-ACS

ACC/AHA and ESC guidelines1-3 recommend an early invasive strategy for patients presenting with non–ST-segment elevation acute coronary syndrome (NSTE-ACS) without life-threatening symptoms but with high-risk features. An early invasive strategy consists of coronary angiography within 24 to 72 hours and subsequent revascularization when indicated.

At ACC.15, Hani Jneid, MD, Baylor College of Medicine, took the position that evidence justifies an early invasive strategy in most patients with ACS. He allowed that there are about 25% of patients at such low risk that an early invasive strategy is not necessary, as well as a small percent of individuals at such high risk that few would argue they need to immediately go to the catheterization laboratory.

That leaves about 70% of patients where there is some debate. Data suggest that an early invasive approach reduces ischemia and hard cardiovascular (CV) outcomes in high-risk patients. Such an approach is safe and reduces length of stay and costs.4

In ISAR-COOL, the idea was that stabilizing ACS patients—cooling off hot plaque—would be beneficial, yet Dr. Jneid said deferral of intervention for prolonged antithrombotic pretreatment did not improve outcomes compared with immediate intervention accompanied by intense antiplatelet treatment.5 He noted, “If a decision to undergo an invasive strategy is undertaken, why procrastinate? Why delay?”

R. Scott Wright, MD, professor of medicine at the Mayo Clinic, argued that evidence dictates a thoughtful and more selective application of an early invasive strategy in patients with NSTE-ACS. Yes, time is myocardium in STEMI and it’s important to get the artery open very quickly, but in patients without ST elevation, Dr. Wright said, “There is more time to appropriately medically manage, stabilize, then cath patients once we have thought carefully about the risk-benefit analysis.”

Take time, he said, for the ‘eye-ball’ test; look at the patient and ask: “Should we intervene with this patient? Is this patient healthy enough to withstand the therapy? Is it appropriate? Are they elderly and to the point where we are not going to offer much of a benefit? If they are younger and higher risk, then certainly we should accelerate care.”

Today, there is more opportunity for tailoring medical therapy and initial medical stabilization with potent DAPT and newer anticoagulants. Clinicians can evaluate the risk-benefit ratio of invasive therapy and apply it when there is a clear indication of potential value.

Looking at the best evidence, randomized trial data from ICTUS (the Invasive versus Conservative Treatment in Unstable coronary Syndromes) trial, for patients presenting with NSTE-ACS and an elevated troponin T, investigators could not demonstrate a benefit of an early invasive strategy in reducing death or MI at 5 years compared with a selective invasive strategy.6 After risk stratification by FRISC score, again the ICTUS investigators could detect no benefit from an early invasive strategy.

Dr. Jneid brought up ICTUS trial, too. Yes, early intervention did not differ greatly from delayed intervention in preventing the primary outcome, but was superior to delayed intervention in high-risk patients (Grace risk score >140).

Dr. Wright said risk is important but there are low-risk scenarios where an early invasive strategy is usually just not necessary, such as ST depression <0.5 mm, modest troponin elevations, and no high-risk clinical features. Likewise, there are situations where comorbidities may elevate the risk of PCI: advanced renal dysfunction, high-risk PCI scenarios, and infectious or inflammatory conditions with significant risks.

Finally, Dr. Wright added, “We have to deal with the disease comprehensively. Our paradigm in 2015 recognizes that unstable CAD is more than a simple unstable plaque or region—it is a systemic issue that necessitates a comprehensive treatment strategy.”

Clopidogrel Pretreatment

Clopidogrel pretreatment is recommended for patients with ACS and stable CAD who are scheduled for PCI, but whether this improves outcomes is unclear. Given that PCI is the treatment of choice for most patients with ACS, these patients need potent antiplatelet drugs with rapid onset of action and low bleeding rates. Does clopidogrel fill that bill in 2015?

A. Michael Lincoff, MD, a professor of medicine at the Cleveland Clinic main campus, argued at ACC.15 that there is strong evidence warranting universal adoption of clopidogrel pretreatment. In a meta-analysis of six randomized controlled trials (RCTs), two observational analyses of RCTs, and seven observational studies, there was no difference in terms of absolute risk for death for pretreatment versus no pretreatment among the 37,814 patients analyzed.7 However, clopidogrel pretreatment was associated with a lower risk of major adverse cardiac events (MACE, here defined as death, MI, urgent target vessel revascularization, and stroke; 9.83% vs. 12.35%; odds ratio [OR]: 0.77; p <0.001).

One argument against the broad use of clopidogrel is the increased risk experienced when patients get shifted off the PCI track and sent for CABG instead. Indeed, guidelines suggest discontinuation of clopidogrel 5 days prior to CABG when possible. Yet when investigators looked at this risk more carefully, the results were surprising. They analyzed 34 studies with 22,584 patients undergoing CABG comparing outcomes in patients with recent clopidogrel exposure compared with those without recent clopidogrel.8

In ACS patients, there was no significant difference in mortality (OR: 1.44; p = 0.07) or post-operative MI (OR: 0.57; p = 0.08) or stroke (OR: 1.23; p = 0.52). Combined MACE (stroke, MI, and death) was not different in the two groups (OR: 1.10; p = 0.43). Reoperation rates were elevated in those on clopidogrel but these rates have diminished over time, and were specifically not different in ACS patients (OR: 1.5; p = 0.13).

The authors explained that previous studies focused on surrogate endpoints and compared higher-risk ACS patients with elective cases. Instead, their meta-analysis suggests that many patients have safely undergone CABG on clopidogrel and surgical expertise is growing.8

Jeffrey S. Berger, MD, director, Center for Cardiovascular Clinical Research and Chairman of Cardiology for Geisinger Health System, Pennsylvania, argued that the evidence that pre-treatment with clopidogrel is beneficial is weak. However, he said, “Statistically significant p values from pooled data derived from dissimilar studies ought to be considered hypothesis generating rather than definitive.” Indeed, he pointed out that the reduction in MACE was largely driven by a reduction in subclinical periprocedural MI.

Sure, subclinical periprocedural MIs cannot be good and are worth avoiding, but what was being avoided in these studies? The guidelines once recommended a CK-MB three times the upper limit of normal be used to diagnose periprocedural MI, but then that was increased to a three- to five-fold increase. (Recently, some have argued that the diagnosis should require a ten-fold increase in CK-MB.) However, the lower threshold was used to diagnose procedural MIs in the meta-analysis, some of which would not qualify as periprocedural MIs today.

What about bleeding? As Dr. Lincoff noted, the meta-analysis comparing pretreatment and no pretreatment showed no significant association between pretreatment and major bleeding (Table).7 Although the observed 18% increase in the relative risk of major bleeding was not statistically significant, there was a 47% increase in minor bleeding that was significant (Table).

(Editor’s note: In the meta-analysis under discussion, minor bleeding events were exploratory safety endpoints and available in only five of the RCTs, producing the increased bleeding risk cited by Dr. Gerber. However, this was not evident in observational analyses of RCTs [OR: 1.01; p = 0.91] or in observational studies [OR: 1.09; p = 0.58] although it should be noted that in these two cases, data were available in only one and two studies, respectively.)

CSWNI Infographic

With door-to-needle times a quality metric that is being met in a high proportion of patients today, then the world we are all operating in today is one of shorter pretreatment times and the slower acting the drug administered (like clopidogrel) the less potential there is for any beneficial effect. Likewise, the more potent and rapidly acting drugs used in the cath lab today (ticagrelor and prasugrel) limit potential benefit from pretreatment.

For patients with NSTE-ACS, Dr. Berger recommends a nuanced approach: pretreatment in nonsurgical patients, those patients at very low risk for ending up in surgery (patent left internal mammary artery, young with a first presentation, and no risk factors that would increase the likelihood of a surgical approach, etc.). Pretreatment should be considered if there is a delay to getting to the lab or a radial approach is planned. On the other hand, “I favor no pretreatment in patients who will be taken rapidly to angiography and who are at ‘increased risk’ of CABG for whom discharge prior to CABG would be unwise.” Also, he does not favor pretreatment in patients with prior ACS, long-standing diabetes, chronic kidney disease, or known mitral valve or peripheral vascular disease.

Tick Tock: Duration of Therapy

Just like love and marriage, first comes stent implantation, then comes dual antiplatelet therapy (DAPT)—with the goal of not birthing any more occlusive lesions, stenoses, or thrombi. So how long is long enough for DAPT? It’s a critical question given that experts are expecting that by 2018, there will be more than 5 million interventions using drug-eluting stents (DES) worldwide.

The DAPT debate goes back to 2006 or so with evidence that for all the acclaim heaped on DES, bare-metal stents outperformed their newer brethren in one important area: reducing rates of stent thrombosis (ST). This was likely due to incomplete endothelialization and continued exposure of stent struts, even 1 year or more after DES implantation, according to Colin Barker, MD, of the Houston Methodist DeBakey Heart and Vascular Center, speaking at ACC.15. Then larger trials turned the notion around; there probably was no difference in ST, but there was a “time dependence” in regard to event rates and stents. For example, in HORIZONS-AMI, early predictors of subsequent ST were STEMIs presenting as stent thrombosis, Killip class III or IV, stent size <3.0 mm, prior MI, or diabetes, but at 1 year and beyond, the primary predictor of late ST was the presence of a DES.9

Sure enough, in a retrospective data analysis that suggested premature discontinuation of antiplatelet therapy proved to be the strongest risk factor for ST, occurring in 29% of patients, more than three times as frequent as the next factor.10 Combined with small studies, this analysis became the foundation of guideline recommendations urging 12 months of DAPT post-stenting.

Newer-generation DES, however, have vastly reduced the concerns of uncovered struts and incomplete endothelialization, showing safer ST results than earlier DES and BMS. But when it comes to safety, DAPT carriers its own issues, primarily with bleeding and subsequent mortality risk. “Yes, it’s better not to bleed. We need to somehow find some middle ground as far as duration of dual antiplatelet therapy, and balance the thrombotic risk with the bleeding risk,” Dr. Barker said plainly.

As Deepak L. Bhatt, MD, MPH, puts it, “How to tailor therapy to the individual patient to incorporate antiplatelets and anticoagulants is extremely challenging with limited data to guide us.” Moreover, the Executive Director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital, Boston, noted that what data are available may be difficult to interpret. In trials evaluating the duration of dual antiplatelet therapy, for example, studies have compared 3 versus 12 months (RESET and OPTIMIZE), 6 or 24 months (PRODIGY and ITALIC), 6 versus 12 months (ISAR SAFE and EXCELLENT), 12 or 36 months (DES-LATE), 12 versus 24 months (SCORE), 12 or 30 months (DAPT and ARCTIC), and 12 versus 48 months (OPTIDUAL). Two of those, SCORE and OPTIDUAL, are still underway, but at ACC.15, Dr. Bhatt said: “To date, these trials have not shown a benefit of extending the duration of dual antiplatelet therapy in relatively lower-risk stenting populations but have shown some degree of bleeding hazard.”

In reviewing the ten randomized controlled trials evaluating different DAPT durations following PCI, Dr. Barker said “most of them did seem to show that if you took all of them in a composite, there was no advantage to an upfront strategy of prolonging DAPT beyond 6 months in reducing thrombotic risk with contemporary drug-eluting stents.” In Europe, these data have led to both behavior and guideline modification such that different stents have received CE mark for shorter DAPT durations; in the case of the Resolute Integrity stent, that duration is 1 month, and thus far no downside has been reported in terms of increased events.

CSWNI Infographic

That doesn’t mean, though, that shorter is always better or preferred. The DAPT study, probably the most robust look yet at antiplatelet therapy duration, took patients with a PCI who had been event-free for 12 months on DAPT and randomized them to an additional 18 months with continued DAPT or placebo plus aspirin.11 So did the additional time prove helpful or harmful? In the case of ST, a co-primary efficacy endpoint, additional DAPT demonstrated a significant reduction in ST at 30 months (0.4% vs. 1.4%; p <0.001). But don’t pop champagne corks yet: as Dr. Barker emphasized, it came with a cost: if you stay on DAPT, you will bleed more; in this trial, incidence of moderate or severe bleeding was significantly greater in the active therapy arm (2.5% vs. 1.6%; p = 0.001).

In trying to distill the messages of these various DAPT duration trials, Dr. Barker devised a quick algorithm on DAPT duration based on the dueling considerations of thrombosis and bleeding risk (Figure 1). What is interesting is that in patients with both high thrombosis and bleeding risk, the original recommendation of 12 months of DAPT still provides the safest duration after PCI. However, in patients with a high bleeding risk and low thrombosis risk, 6 months or less is a good guideline and, he said, some patients may only need 1 to 3 months.

Don’t be quick to discontinue DAPT, said Robert A Byrne, MBBCh, PhD, German Heart Center, Bavaria, at the 2015 EuroPCR meeting. He concluded that the data remain inconclusive. On one hand there is the OPTIMIZE trial, which randomized 3,119 patients with stable CAD or low-risk ACS implanted with zotarolimus-eluting stents (ZES) to 3 or 12 months of DAPT.12 OPTIMIZE demonstrated noninferiority in terms of the primary endpoint of all-cause death, MI, stroke, or major bleeding (p = 0.002) with no significant increase in ST.

Other investigators looked at DAPT interruption and found that in ZES patients who had their therapy interrupted for >1 day during the first month of therapy, such interruptions were associated with a high risk of adverse outcomes and ST, particularly when the interruption was extended.13 Interruptions between 1 and 12 months produced low event rates. The discrepancy points to a need for randomized trials to determine whether early temporary or permanent interruption—or discontinuation—of DAPT is truly safe.

Seeing Double or Triple

Patients who receive a stent (or five) who are on DAPT but face the extra burden of atrial fibrillation (AF) add a third agent to the mix and new wrinkle to their therapy. The third agent is an antithrombotic—warfarin or one of the newer oral anticoagulants (OAC) such as apixaban, dabigatran, or rivaroxaban—and the wrinkle is increased bleeding risk.

Risk assessment scores such as CHA2DS2-VASc for stroke and HAS-BLED for bleeding offer clinicians the ability to better determine which antithrombotic agent and at what dose might best benefit a particular patient with AF. But since antithrombotics and antiplatelets attack different mechanisms of clotting both end up contributing to bleeding—a big concern when considering triple therapy. But for patients with AF, the bigger issue may be the long-term risks imposed by atrial fibrillation rather than the relatively shorter-term concerns from stenting.

The area where most debaters agree: duration of triple therapy should be as short as possible. While ACC/AHA guidelines for AF simply say “minimize” how long one takes three agents, European guidelines offer more concrete time frames—albeit acknowledging the evidence is lacking.

At EuroPCR, Jean-Phillipe Collet, MD, PhD, Institut de Cardiologie de la Pitié-Salpêtrière, Paris, pointed to European guidelines issued in 2014 for revascularization and AF that delineate a patient’s stroke and bleeding risk in considering length of triple therapy. For patients with a HAS-BLED ≥3 (i.e., higher bleeding risk), both guidelines recommend limiting triple therapy to 1 month irrespective of stroke risk or clinical setting (stable coronary artery disease, DES or BMS), to be followed by dual therapy consisting of an oral anticoagulant and either aspirin or clopidogrel. The Euro AF guidelines go a step further, limiting initial therapy to just an oral anticoagulant plus aspirin or clopidogrel in selected patients with high bleeding risk.

Revascularization guidelines suggest a 1-month triple regimen may be sufficient for patients with stable disease, higher stroke risk, and lower bleeding risk, but a patient with ACS may need to stay on triple therapy for 6 months. The AF guidelines recommend 6 months of triple therapy for all patients with low bleeding risk; then, for patients with higher stroke risk (CHA2DS2-VASc ≥2), potentially extend triple therapy to 12 months depending on patient characteristics.

Any Role for GP IIb/IIIa Inhibitors?

In the modern era of more potent P2Y12 inhibitors and the antiplatelet/anticoagulant bivalirudin, the role of glycoprotein (GP) IIb/IIIa inhibitors for routine use during PCI for ACS has become a topic of debate. Venu Menon, MD, director of the coronary care unit, Cleveland Clinic, argued at ACC.15 that there is no reason to adjust the current U.S. guidelines for NSTE-ACS, which were published in 2014.3

Class I:
In patients with NSTE-ACS and high-risk features (e.g., elevated troponin) not adequately pretreated with clopidogrel or ticagrelor, it is useful to administer a GP IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or high-dose bolus tirofiban) at the time of PCI. (Level of Evidence [LOE]: A)

Class IIa:
In patients with NSTE-ACS and high-risk features (e.g., elevated troponin) treated with unfractionated heparin (UFH) and adequately pretreated with clopidogrel, it is reasonable to administer a GP IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or high-bolus dose tirofiban) at the time of PCI. (LOE: B)

Class IIb:
In patients with NSTE-ACS treated with an early invasive strategy and dual antiplatelet therapy with intermediate/high-risk features (e.g., positive troponin), a GP IIb/IIIa inhibitor may be considered as part of initial antiplatelet therapy. Preferred options are eptifibatide or tirofiban (LOE: B)

Sigmund Silber, MD, Munich, Germany, disagreed, finding little role for GP IIb/IIIa inhibitors in pretreatment in the contemporary era of ACS management where, he said, the role of these agents has become “more and more questionable.” Bleeding is a serious event with serious long-term implications, he stressed, and should always be avoided if possible. The latest ESC guidelines (2014) recommend GP IIb/IIIa use during PCI in patients with STEMI or -NSTEMI but only for bailout situations, with not particularly strong evidence supporting it (Class IIa; LOE C). In contrast, these agents clearly are more broadly recommended in US guidelines.

There is agreement in one area: pretreatment with GP IIb/IIIa agents is recommended in Europe and the U.S. for high-risk patients undergoing PCI for STEMI (Class IIb; LOE B for each). Nevertheless, for patients undergoing PCI for NSTEMI, pretreatment is not recommended in Europe but is in the US (IIb B).

Overall, Dr. Sigmund said, the European guidelines do not have to be revised; however, he is convinced US experts should reconsider their present recommendations.

Pump You Up… Or Not

Cardiogenic shock remains a serious complication of acute MI despite early revascularization. Intra-aortic balloon pump (IABP) counterpulsation offers mechanical hemodynamic support to these patients and until recently had a Class I recommendation in this setting in both European and U.S. guidelines.

CSWNI Infographic

But those original recommendations came largely from registry data and mounting evidence from clinical trials has deflated the euphoria over IABP use. For example, the IABP-SHOCK II randomized 600 acute MI patients with cardiogenic shock to IABP or no IABP after early PCI or CABG.14

At 30 days, only slightly fewer patients receiving counterpulsation had survived (39.7% vs. 41.3%; p = 0.69) and there was no difference in terms of major bleeding, sepsis, stroke, hemodynamic stabilization, and other measures. In the short term, IABP added no net benefit to patient survival—and this finding didn’t change at 12 months either.

These results contributed to a downgrading in both sets of guidelines, such that IABP is now a Class II recommendation in this setting; the ACCF/AHA guidelines further award a Class IIb recommendation to the statement “Alternative LV assist devices for circulatory support may be considered in patients with refractory cardiogenic shock.” Presenting at SCAI 2015 on trends in use of mechanical circulatory support (MCS) devices, Shikhar Agarwal, MD, an interventional cardiology fellow at the Cleveland Clinic’s Heart and Vascular Institute, noted that in nationwide registry data of 414,367 inpatients with STEMI (sampled between 2003 and 2012), 38,213 or 9.2% used IABP and 830 (0.2%) used other MCS devices. However, use of IABP peaked in 2009 (Figure 2) and has been declining while use of other devices, particularly percutaneous assist devices such as Tandem Heart and Impella, began shooting up at that same time. This coincides with a rise in incidence of timely PCI in cardiogenic shock patients over the decade of the study, where use of IABP led to a significant increase in in-hospital death (29.1% vs. 23.9%; p <0.001) compared to no IABP, as was found in IABP-SHOCK II. However, when PCI was not timely, IABP significantly reduced mortality during hospitalization (34.7% vs. 51.6%; p <0.001).

Balloon counterpulsation has had a pin stuck in it as well. In the Counterpulsation to Reduce Infarct Size Pre-PCI-Acute Myocardial Infarction (CRISP-AMI) trial, researchers wanted to see if routine IABP placement prior to PCI in patients with anterior STEMI but without shock would reduce MI size.15 Spoiler alert: It wouldn’t, although it did show benefit in patients with persistent ischemia. Overall, though, 8.5% of patients in the PCI-alone group crossed over to rescue IABP therapy, leading the researchers to speculate that IABP might serve as a “standby strategy” during primary PCI in high-risk anterior STEMI patients.

While some are ready to write off IABP in many settings, more recent data demonstrate some differences, such as the Balloon Pump–Assisted Coronary Intervention Study (BCIS-1), where elective IABP was associated with a 34% relative reduction in all-cause mortality compared with unsupported PCI in patients with severe ischemic cardiomyopathy.16

Perhaps IABP can redeem itself in subsets of patients. That was the tack taken at the 2015 EuroPCR meeting by Divaka Perera, MD, Kings College London, and first author of BCIS-1. But to do so, one must consider the interaction or the relationship between pressure and flow, specifically, autoregulation. When he and colleagues administered intracoronary adenosine to temporarily disable auto-regulation and considered microvascular resistance, he noted that “just as autoregulation theory would predict, when your autoregulation is functioning and you turn the balloon pump on, microvasculature resistance goes up. And when you disable it, there’s hardly any change at all.” Additionally, when autoregulation is on, the pump does not significantly change flow, but the reverse is true when autoregulation is off.

“Somehow, we have to get our heads around the fact that the heart and the microcirculation seems to resist that increase in pressure if it’s able to regulate itself,” Dr. Perera added. Put another way, when autoregulation is exhausted or dysfunctional, augmenting pressure with an IABP may enhance myocardial perfusion in such scenarios as persistent ischemia/no-reflow, marked hypotension or shock, or downstream of a critical coronary stenosis.

In reporting on a single-center clinical experience following Dr. Perera’s talk, Marc Cohen, MD, Newark Beth Israel Medical Center, Newark, New Jersey, noted that use of a 50 cc “mega” balloon in 150 consecutive patients (100 with cardiogenic shock) produced significant improvements in most bedside clinical parameters as well as a hospital survival rate of at least 67% in the patients with cardiogenic shock. This ‘bigger may be better’ aspect of balloons also was supported by Navin K. Kapur, MD, director of interventional research laboratories at Tufts Medical Center, Boston, Massachusetts, in a presentation at the 2015 SCAI meeting in San Diego. In comparing patients receiving counterpulsation through 50 cc versus 40 cc balloons, Dr. Kapur and colleagues found the larger device lead to greater systolic unloading and diastolic augmentation.17

While Dr. Cohen said he appreciates the “almost immediate nature of being able to deploy counterpulsation” boosting its use in sick patients, clinicians need to recognize that the benefit is not likely universal. As Simon Redwood, MD, president, British Cardiovascular Intervention Society, and professor of interventional cardiology, King’s College London, put it, the theme seems to be building that pumps only work in the presence of persistent ischemia or critical stenosis.

Dr. Cohen added, “I think it would be worthwhile for those of us that do this work to look at the people that are responders versus non-responders the way we look carefully at clopidogrel responders and non-responders. I think that’s a fascinating situation where we’re just beginning to scratch the surface,” he said.

New Tools for Digging into Diagnostics

In some ways, interventional cardiologists are almost like cartographers, mapping the intricate landscape of the complex anatomy of humans. And just as the instruments used to produce and visualize maps have evolved dramatically over time—how many of us have strolled down the streets of our childhood via Google Earth?—so too have the tools of physiologic assessment. And those clinicians not using the newer tools representing the alphabet soup of everything from iFR to NIRS to IMR are “practicing old interventional cardiology and I think you better reconsider your career choice,” said Morton J. Kern, MD, professor of medicine at University of California at Irvine, Orange, CA, in a presentation at SCAI.15.

His belief is that “controversies in cardiology are common because we lack the information and haven’t developed the right tools,” but when it comes to determining whether a lesion requires intervention, a number of tools are now available. Some may shy away, he noted, because “the math behind some of these indices of physiology can be complex, but in general they are not; they’re measurements of simple pressure and flow and computations can derive the information to address some of the problems.”

Furthermore, developments are helping to put to rest concerns and controversies such as whether physiology can be obtained in the absence of hyperemia. Dr. Kern pointed to the instantaneous wave-free ratio (iFR) as a potential solution to resolve the controversy, noting that RESOLVE found an 80% correlative predictive value with fractional flow reserve (FFR) that rose to ≥90% in a subset of lesions.18 The DEFINE FLAIR study is enrolling patients and will compare iFR and FFR in a randomized multicenter trial of deferred stenting in non-significant lesions with a primary outcome of composite of death, MI, and unplanned revascularization at 1 year.

Also available today: newer—and better—imaging tools. As to the two most often used—optical coherence tomography (OCT) and intravascular ultrasound (IVUS)—Dr. Kern said “you can see more easily with OCT and outcomes data are available with IVUS.” But one thing he also attributes to IVUS: it changes operator behavior because now the operator sees “‘I need a bigger stent’ or ‘I need a longer stent’ or ‘I found malapposition.’ All this is true—but the question is, does this translate to better patient outcomes?” That remains a “missing link” in terms of data from large-scale outcome studies.


  1. O’Gara PT, Kushner FG, Ascheim DD, et al. J Am Coll Cardiol. 2013;61:e78-140.
  2. Windecker S, Kolh P, Alfonso F, et al. Eur Heart J. 2014;35:2541-619.
  3. Amsterdam EA, Wenger NK, Brindis RG, et al. J Am Coll Cardiol. 2014;64:e139-228.
  4. Lamy A, Tong WR, Bainey K, Gafni A, et al. Can J Cardiol. 2015;31:314-9.
  5. Neumann FJ, Kastrati A, Pogatsa-Murray G, et al. JAMA. 2003;290:1593-9.
  6. Damman P, Hirsch A, Windhausen F, et al. J Am Coll Cardiol. 2010;55:858-64.
  7. Bellemain-Appaix A, O’Connor SA, Silvain J, et al. JAMA. 2012;308:2507-16.
  8. Nijjer SS, Watson G, Athanasiou T, et al. Eur Heart J. 2011;32:2970-88.
  9. Brodie B, Pokharel Y, Garg A, et al. JACC Cardiovasc Interv. 2012;5:1043-51.
  10. Iakovou I, Schmidt T, Bonizzoni E, et al. JAMA. 2005;293:2126-30.
  11. Mauri L, Kereiakes DJ, Yeh RW, et al. N Engl J Med. 2014;371:2155-66.
  12. Feres F, Costa RA, Abizaid A, et al. JAMA. 2013;310:2510-22.
  13. Silber S, Kirtane AJ, Belardi JA, et al. Eur Heart J. 2014;35:1949-56.
  14. Thiele H, Zeymer U, Neumann FJ, et al. N Engl J Med. 2012;367:1287-96.
  15. Patel MR, Smalling RW, Thiele H, et al. JAMA. 2011;306:1329-37.
  16. Perera D, Stables R, Clayton T, et al. Circulation. 2013;127:207-12.
  17. Kapur NK, Paruchuri V, Majithia A, et al. J Invasive Cardiol. 2015;27:182-8.
  18. Jeremias A, Maehara A, Généreux P, et al. J Am Coll Cardiol. 2014;63:1253-61.

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