Clinical Conference Proceedings: IAGS 2022 Summary Document

IAGS 2022 Session 1: Coronary Session 1—Elective PCI

1.1 Percutaneous Coronary Intervention (PCI) for Quality of Life (QoL) in Stable Ischemic Heart Disease (SIHD)

Problem Presenter: Kirk Garratt, MD

Statement of the problem or issue

Elective PCI was embraced for many years as a means of reducing risk of serious adverse cardiovascular events among patients with SIHD. To test this hypothesis, multiple randomized clinical trials (RCTs) comparing optimal medical therapies (OMTs) against OMT+PCI were conducted over several decades, initially hoping to demonstrate the extent of presumed benefit with PCI. Instead, these RCTs found, with reasonable consistency, that patients with SIHD do just as well with OMT alone as with OMT+PCI, at least for several years. As these trials were completed, concern then turned toward the risks associated with PCI: did premature use of PCI expose patients to the possibility of harm unnecessarily? ­Consistent with findings from earlier trials, the most recent relevant RCT, the ISCHEMIA trial (Maron, 2020),¹ found that an initial strategy of OMT yielded similar rates of a composite adverse outcome as an initial strategy of PCI, over an average follow-up of more than 3 years. Most patients (77%) in ISCHEMIA had multivessel disease, and about three-fourths of patients had a screening cardiac CT scan before enrollment and were excluded if they had either no disease, very severe disease, or left main disease. Interestingly, ISCHEMIA did not find any relationship between baseline ischemic burden and the degree of benefit with invasive therapies; in fact, adverse event rates did not increase in parallel with the extent of coronary disease or ischemia in either treatment group. The takeaways from ISCHEMIA were: (1) early use of PCI in the enrolled SIHD patients did not lower risk of aggregated ischemic events; (2) early use of PCI was not associated with increased risk of meaningful harm, although PCI uniquely exposes patients to risk of procedural MIs; and (3) neither the extent of coronary disease nor the ischemic burden defined by stress testing helped identify patients who might be best suited for an invasive care plan. The ability of PCI to improve QoL more than medical therapies alone has also been called into question: the ORBITA trial (Al-Lamee, 2018)² found PCI offered no improvement in exercise tolerance among SIHD patients with single-vessel coronary artery disease receiving OMT. Contrary to ORBITA, ISCHEMIA found QoL was improved with early use of PCI, although the benefit was largely seen among patients with frequent angina at baseline (Spertus, 2020).³ The safety of an initial conservative approach, coupled with questions about the ability of PCI to enhance QoL consistently, has led some to suggest that a symptom-driven care pathway, developed without any anatomic or physiologic studies and which reserves use of PCI for only those patients with refractory symptoms, is preferable to an ischemia-based or anatomy-based approach, since practitioners won’t be tempted to reach for PCI if they are worried by the diagnostic study findings (Mancini and Boden, 2020).⁴ So, is this a reasonable way to approach SIHD patients?

Gaps in knowledge

Left main disease was found in approximately 5% of those screened for enrollment in ISCHEMIA. If these patients are at higher risk with medical therapies alone, and therefore deserving of consideration for revascularization (the pretext for excluding them from randomization in ISCHEMIA), then reliance solely on symptoms may put a small but not insignificant number of patients at unnecessary risk. On the other side, about 18% of screened ISCHEMIA patients were found to have no obstructive coronary artery disease by cardiac CT; so, exposure to cardiac medications, likely to be ratcheted up as noncardiac symptoms fail to improve, offers risk without benefit. In other words, the safety of a care plan that relies on no anatomic or physiologic data is undefined. Also undefined is the optimal utility of PCI in reducing the frequency and intensity of angina among patients with multivessel disease who improve with medications but are still having occasional angina. In this regard, it’s worth noting that ISCHEMIA found reductions in angina frequency with early PCI even among patients with angina occurring only a few times per month, and of course clinical experience suggests PCI is useful in this type of patient. Should patients be required to endure activity-limiting ischemic symptoms as their medications are maximized, when PCI might restore them to full or nearly full function with fewer daily medications? Finally, the observation from ISCHEMIA that spontaneous myocardial infarction rates are reduced if PCI is used early in the care plan for SIHD, raises questions about whether early invasive therapy, coupled with guideline-directed medical therapies, may offer benefits that lie beyond angina relief.

Possible solutions and future directions

Additional RCTs in the future for this patient population seem unlikely at this time, but if one is undertaken, the aims and endpoints of the RCT should change. The question is no longer whether an initial strategy of medical therapies alone offers sufficient safety (as measured by composite ischemic endpoints), or whether PCI is potentially too hazardous to use early. The question is: how can PCI be best incorporated into a comprehensive care plan, based on a background of OMT, to optimize clinical outcomes including QoL over a long time period. ISCHEMIA, the largest and most contemporary RCT on this topic, found no increased harm with a strategy of early invasive care for SIHD patients, and it holds the possibility for benefit evolving after 24 months or so, but with the caveat that PCI exposes patients to the risk of early periprocedural MIs. Periprocedural MIs have not been associated with the same degree of morbidity or mortality as spontaneous MIs; nonetheless, a periprocedural MI is an MI, so a blunt instrument for measuring events will find fault with an early invasive strategy. MI definitions with appropriate sensitivity and specificity, and that stratify by MI type, can minimize this problem, which is the reason for the definitions used in the ISCHEMIA trial. Advocates for conservative care have complained that more sensitive MI definitions would have ruled PCI more hazardous than the conservative care plan. While this concern has been thoroughly reviewed by the ISCHEMIA trial workgroup (Chaitman, 2021),⁵ the debate over appropriate thresholds for capturing procedural MIs remains ongoing. Defining how MI thresholds of varying sensitivity correlate with clinical outcomes (including QoL measures), and not just event rates, would be a suitable focus area for future trials. Intriguingly, ISCHEMIA found a reduction in the occurrence of spontaneous MIs with early use of invasive therapy during 3 years of follow-up. While not definitive, this observation raises the possibility that performing early PCI may mean accepting the risk of less perilous periprocedural MIs in exchange for fewer higher-risk spontaneous MIs later. Perhaps one unintended consequence of ISCHEMIA is the re-energized focus on cardiac CT. The spatial and temporal resolution of modern cardiac CT scanners has improved substantially over older models. While the ISCHEMIA trial was enrolling patients, cardiac CT-FFR methods were perfected and then made commercially available. It seems likely that going forward, despite the lack of correlation found between disease severity or ischemic burden and outcomes found in ISCHEMIA, clinicians will base their recommendations according to those clinical features that have always been trusted indicators of risk, and which are biologically plausible as being related to risk. For this reason, a symptom-driven care plan is unlikely to dominate, but a gradual shift away from traditional electrocardiographic, echocardiographic, or nuclear-based diagnostic cardiac testing and toward a more cardiac CT-based testing approach is expected.

References

1. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med. 2020;382(15):1395-1407. Epub 2020 Mar 30. doi:10.1056/NEJMoa1915922

2. Al-Lamee R, Thompson D, Dehbi HM, et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomized controlled trial. Lancet. 2018;391(10115):31-40. doi:10.1016/S0140-6736(17)32714-9

3. Spertus JA, Jones PG, Maron DJ, et al. Health-status outcomes with invasive or conservative care in coronary disease. N Engl J Med. 2020;382(15):1408-1419. Epub 2020 Mar 30. doi:10.1056/NEJMoa1916370

4. Mancini GB, Boden WE. Diagnostic implications in the aftermath of the ISCHEMIA trial. Am J Cardiol. 2020;125(9):1438-1440. Epub 2020 Feb 12. doi:10.1016/j.amjcard.2020.01.039

5. Chaitman BR, Alexander KP, Cyr DD, et al. Myocardial infarction in the ISCHEMIA trial. Circulation. 2021;143(8):790-804. doi:10.1161/CIRCULATIONAHA.120.047987

1.2 Plaque Modification: When to Apply Ablative vs Disruptive Therapies

Problem Presenter: Michael Cowley, MD

Statement of the problem or issue

In the beginning we only had balloons available to modify plaque, that is, plain old balloon angioplasty (POBA). In those days, plaque-modification options were simple: smaller balloons were used to “predilate,” and larger, noncompliant balloons were used to “postdilate.” Starting in the 1990s, the era of “new devices” began. We had directional atherectomy, rotational atherectomy, cutting balloons, and excimer laser, all of which were developed in that era. Some of these survived into the 2000s. Currently, we have rotational atherectomy (RA), orbital atherectomy, cutting balloon, excimer laser, and the newest technology, shockwave lithotripsy. We can group these devices into classes. The Ablative Class includes both rotational and orbital atherectomy devices. The Disruptive Class includes cutting balloons and shockwave lithotripsy. The excimer laser overlaps these classes because it has both ablative as well as disruptive actions (Table 1).

We have learned through experience that these devices are rarely the primary treatment modality, but instead are used as adjuncts to another primary treatment, which usually is a stent, and more specifically, a drug-eluting stent.

Gaps in knowledge

We don’t know exactly what the adjunctive role of these devices should be. We are trying to understand when and how plaque modification with these devices should be done in order to achieve a successful immediate procedure with a durable, long-lasting result. Situations where plaque modification techniques might be considered include the following: moderate to heavy calcification, provisional vs direct lesion approaches, and when unfavorable angiographic features are present, for example, when there is marked angulation or severe tortuosity in an artery. Of course, failure to cross a lesion, or failure to predilate the lesion sufficiently to permit passage of the primary treatment catheter, are examples of situations where additional, adjunctive therapies are needed (Table 2).

Another gap area in our knowledge is the matching of devices to situations. Some situations appear to favor one class of device, while other situations appear to favor another class (Table 3).

While we know there are many situations where one or more of these unfavorable conditions listed in Table 2 exist, we are still lacking strong evidence on best practices.

Possible solutions and future directions

The newest technology added to our armamentarium is the shockwave lithotripsy device, manufactured by Shockwave Medical. It was approved for peripheral artery use in 2016, and approved for coronary use in February 2021.¹ The device uses bursts of energy to emit 50 atm pressure waves that create microfractures in calcified plaque. It appears to be simple, safe, effective, and also expensive. The question of shockwave lithotripsy expense brings up the concept of “value.” Is there a valid “value” equation for use of these devices, and if so, in what situations? The larger question, though, still remains the same: what are the respective roles of these adjunctive devices? Only further research will reveal answers.

Reference

1. Liang B, Gu N. Evaluation of the safety and efficacy of coronary intravascular lithotripsy for treatment of severely calcified coronary stenoses: evidence from the Serial Disrupt CAD trials. Front Cardiovasc Med. 2021;8:724481. eCollection 2021. doi:10.3389/fcvm.2021.724481

1.3 Bifurcation Lesions: What Are the Optimal Stenting Strategies, and Will Drug-Coated Balloons Change Them?

Problem Presenter: J. Dawn Abbott, MD

Statement of the problem or issue

In large clinical studies and registries, bifurcation lesions consistently account for approximately 10%-15% of percutaneous coronary intervention (PCI) procedures. Bifurcation anatomy in clinical trials historically was categorized in simplified manner according to the Medina classification, which described involvement of the main vessel (MV) and the side branch (SB) using a 0-1 binary scheme. More recently, assessing bifurcation complexity has evolved, using the DEFINITION criteria, to include additional characteristics that help predict postprocedural major adverse cardiac events, and facilitate selection of a 2-stent or provisional-stent strategy. Considerable debate exists on this selection of optimal bifurcation stenting strategy. However, a provisional approach with proximal optimization technique is generally accepted as the favored initial strategy if the risk of SB occlusion is low. Due to unclear thresholds for defining SB significance, there is potential for overuse of 2-stent strategies. Achieving optimal stent expansion and final configuration using intracoronary image guidance is likely more important than the specific 2-stent technique employed. Further, key modifications to 2-stent strategies like double-kiss crush and double-kiss culotte have improved procedural and clinical outcomes. Emerging data support use of drug-eluting balloon (DEB) over plain old balloon angioplasty (POBA) for the SB in a provisional approach when drug-eluting stents are used for the MV.

Gaps in current knowledge

Knowledge gaps in bifurcation PCI are numerous and span anatomic phenotyping all the way to procedural optimization techniques. Noninvasive stress testing and imaging methods for ischemia detection do not readily delineate SB significance regarding size of distal myocardium at risk. Although the DEFINITION criteria are more comprehensive than Medina for differentiating simple from complex bifurcation lesions, it is unclear if use of 2-stent strategies will prevail even in complex anatomy given the apparent superiority of DEB, and whether availability of DEB might limit the need for up-front routine 2-stent techniques and enhance provisional approaches. How SB “compromise” is defined also needs clarification, including whether acute ischemic signs and symptoms, visual lesion and vessel assessment, and hemodynamic measurements can be translated into acute procedural success and improved longer-term clinical outcomes. A further important question here is whether SB compromise should be defined similarly for DEB and POBA. Intuitively, use of intracoronary imaging should result in procedural optimization and reduced risk of target-lesion failure, but which imaging modality and its enhancements (automated image interpretation, coregistration, etc) is preferred is unknown. With the dynamic nature of bifurcation PCI, the need for operator adaptation to the various outcomes of each of the numerous technical steps is required. How operator experience relates to outcomes for bifurcation lesions has not been examined but will need to be. Whether computational modeling or artificial intelligence (AI) can guide decisions in bifurcation PCI remains to be examined broadly clinically, but it has begun to be conceptually developed.

Possible solutions and future directions

Although not widely used currently, commercially available stress-rest imaging modalities that could assess SB disease specifically for significance include PET-CT and FFR-CT. In the future, coupling lesion-specific anatomy with myocardial blood flow might become standard, and perhaps alert the interventionalist to the highest-risk bifurcation cases. Until that time, angiographic scoring systems that estimate myocardium at risk, along with an intraprocedural assessment of acute ischemia, can be used to guide decisions on SB significance and need for intervention. With respect to the benefits of intraprocedural guidance using high-definition imaging, the findings of the 1200 patient OCTOBER (European Trial on Optical Coherence Tomography Optimized Bifurcation Event Reduction) trial are eagerly awaited (ClinicalTrials.gov identifier: NCT03171311). In this trial, which has nearly completed enrollment, randomization is stratified by bifurcation location (left main or non-left main) and by intended treatment strategy (provisional or 2-stent technique). Patients are randomized 1:1 to systematic OCT guidance using 1 of 5 complex stent implantation techniques, or to standard treatment with angiographic guidance and optional use of intravascular ultrasound. Recent advances in software for assessing coronary hemodynamics, such as AptiVue (Abbott), can provide operators with real-time feedback on stent expansion, as well as with nonhyperemic indices to assess ischemia, which can be applied to bifurcation PCI. Potential areas where AI can be applied in bifurcations include helping define optimal stent geometry, MV stent sizing, risk of SB compromise, and the suitability for dedicated bifurcation stent platforms or 2-stent techniques. Computational simulations of bifurcation PCI that utilize angiography-OCT fusion and plaque material properties for 3D patient-specific reconstruction are possible; however, at this time they are performed off-line rather than in real time. In the future, libraries of patient anatomies can be examined using computational simulations to derive possible treatment algorithms based on the expertise of practiced operators. The application of DEB to bifurcation PCI may reduce the problem of SB target-lesion recurrences, but this only scratches the surface of improving outcomes in this common lesion subset. For now, operators are encouraged to understand and optimize the stent techniques they currently are using in practice.

IAGS 2022 Session 2: Structural Session 1—Aortic Valve

2.1 TAVR and PCI: Which Lesions and in Whom?

Problem Presenter: Janarthanan Sathananthan, MD

Statement of the problem or issue

Patients undergoing transcatheter aortic valve replacement (TAVR) often have concomitant coronary artery disease (CAD). For example, in TAVR registries, prevalence of CAD varies from 28%-74%. Furthermore, since the presence of CAD is a determinant of surgical risk, its prevalence will vary according to the surgical risk of patients in any chosen series. In randomized, controlled trials of TAVR, the prevalence of concomitant CAD varies from 81% (patients at extreme risk) to approximately 60% (those at intermediate risk) to as low as 15% (patients at low surgical risk). Among TAVR patients who have CAD, disease burden varies widely too, and is not always insignificant. In one meta-analysis, disease of the left main or left anterior descending artery was present in 11% and 50% of participants, respectively.¹

There are contradictory results regarding the association between CAD and clinical outcomes with TAVR, as reported in 2 meta-analyses.^2,3 While there is no consistent relationship between the presence of CAD and outcomes, whenever CAD is detected, there is a potential impact based on its overall burden. Patients with a high SYNTAX score (>22) have been shown to have worse outcomes after TAVR than those with a low SYNTAX score.⁴ ­Revascularization may be beneficial in these patients. Of note, the current studies assessing the impact of CAD are predominantly from TAVR patients at intermediate or high surgical risk. The impact of concomitant CAD in low-risk TAVR patients who are likely to have a longer life expectancy is poorly understood. Following TAVR, patients may present with an acute coronary syndrome (ACS), and may require emergent coronary angiography and PCI. Unfortunately, there are limited data on rates of ACS after TAVR. One series suggests a rate as high as 10% at a median follow-up of 25 months after TAVR.⁵ However, this series was in a group of patients with a high rate (68%) of pre-existing CAD, which may have contributed to a higher rate of ACS following TAVR.

Gaps in knowledge

In patients who have concomitant significant CAD and aortic stenosis, there is uncertainty about the benefits and optimal timing of revascularization for those who are candidates for TAVR. Current guidelines recommend that PCI may be considered for those with a coronary artery stenosis of >70%. However, these recommendations are based on very limited data, and the benefit of coronary revascularization remains uncertain. Importantly, the recommendation for coronary artery bypass grafting at the time of surgical AVR is also based on a low level of evidence. Additionally, published studies on PCI in TAVR patients are limited by small numbers, heterogenous design, and selection bias. A large RCT is needed to define the role and benefit of PCI in TAVR patients with concomitant CAD.

Possible solutions and future directions

The COMPLETE TAVR study (A Randomized, Comparative Effectiveness Study of Staged Complete Revascularization with PCI to Treat Coronary Artery Disease vs Medical Management Alone in Patients with Symptomatic Aortic Valve Stenosis undergoing Elective Transfemoral Transcatheter Aortic Valve Replacement; NCT04634240) will determine whether, on a background of guideline-directed medical therapy, a strategy of complete revascularization involving staged PCI using drug-eluting stents to treat all suitable coronary artery lesions is superior to a strategy of medical therapy alone in reducing the composite outcome of cardiovascular death, new myocardial infarction, ischemia-driven revascularization or hospitalization for unstable angina or heart failure in patients who have undergone successful elective TAVR. This large trial with 4000 study participants and over 100 sites will help address this important clinical question.

References

1. Faroux L, Guimaraes L, Wintzer-Wehekind J, et al. Coronary artery disease and transcatheter aortic valve replacement: JACC state-of-the-art review. J Am Coll Cardiol 2019;74(3):362-372. doi:10.1016/j.jacc.2019.06.012

2. Stefanini GG, Stortecky S, Wenaweser P, Windecker S. Coronary artery disease in patients undergoing TAVI: why, what, when and how to treat. EuroIntervention. 2014;10(Suppl U):U69-U75. doi:10.4244/EIJV10SUA10

3. D’Ascenzo F, Verardi R, Visconti M, et al. Independent impact of extent of coronary artery disease and percutaneous revascularisation on 30-day and one-year mortality after TAVI: a meta-analysis of adjusted observational results. EuroIntervention. 2018;14(11):e1169-e1177. doi:10.4244/EIJ-D-18-00098

4. Alperi A, Mohammadi S, Campelo-Parada F, et al. Transcatheter versus surgical aortic valve replacement in patients with complex coronary artery disease. JACC Cardiovasc Interv. 2021;14(22):2490-2499. doi:10.1016/j.jcin.2021.08.073.

5. Faroux L, Munoz-Garcia E, Serra V, et al. Acute coronary syndrome following transcatheter aortic valve replacement. Circ Cardiovasc Interv. 2020;13(2):e008620. Epub 2020 Jan 29. doi:10.1161/CIRCINTERVENTIONS.119.008620

2.2 TAVR Durability: What Is It Now and What Do We Need?

Problem Presenter: Christopher U. Meduri, MD

Statement of the problem or issue

The first accurate drawings of human cardiac valves were made by Leonardo DaVinci in 1512 and are captured in his notebooks (Figure 1). Leonardo also used wax injections to take molds of the aortic valve of an ox’s heart. Discovering that immediately above the aortic valve leaflets is a widening of the root of the aorta (the sinus of Valsalva), Leonardo made a glass model of that section. He noted he could “see in the glass what the blood does in the heart when it closes the little doors of the heart.” By pumping water with a suspension of grass seeds through the glass model, Leonardo observed turbulent eddies in the sinus, which he concluded were responsible for opening out the cusps when blood flow through the valve ceased after each heartbeat.^1,2

Despite this impressive early understanding, it wasn’t until 1954 that Lilliehei performed the first aortic valve replacement using a mechanical prosthesis, and not until the 1970s that the first bioprosthetic valve replacement was performed. Of course, in 2002 the history of aortic valve replacement changed forever when the first human clinical transcatheter aortic valve replacement (TAVR) procedure was performed (Figure 2).

Generally, in the early phase of its clinical application, TAVR was performed only in high-risk patients, which meant older patients with moderate life expectancy. In the past 2 decades it was learned that lower- and intermediate-risk patients also benefit from TAVR, and this meant younger-aged patients with longer life expectancy (Figure 3). This has led to a large need to identify methods to make TAVR valves last a lifetime for patients, ie, become more durable.³

Gaps in knowledge

Data from several sources reveal that TAVR, as well as surgical valves, deteriorate beyond 5 years, and so, the question remains, what can be done about it?⁴

Possible solutions and future directions

Possibilities to improve valve durability come from 2 primary areas: tissue science and valve design (Figure 4).

Tissue science has seen very little progress until recently. The Resilia valve from Edwards Lifesciences has removed most of the glutaraldehyde from the tissue, a known factor in valve leaflet calcification.⁵ Additionally, Anteris Technologies has developed a new TAVR using an engineered collagen tissue (called ADAPT) that is free of glutaraldehyde as well as DNA, both significant factors in leaflet calcification. Novel polymers such as synthetic PTFE are used in Foldax’s new TAVR valve.

In the other primary area, there is much room for growth and evolution in valve design. Will supra-annular valves be more durable than standard intra-annular valves? Will designs that increase sinus washout enhance durability? How can stent frame geometry be optimized to further enhance valve durability? Are there ways to modify leaflet design to reduce mechanical stress?

As the focus on lifetime management of valve patients grows, we can hope that these and other innovations will help us treat our patients more effectively for much longer ­periods—even a lifetime.

References

1. Keele K, Pedretti C. Leonardo da Vinci: Corpus of the Anatomical Drawings in the Collection of Her Majesty the Queen at Windsor Castle, 2 vols & facsimiles, London 1979-80 – RL 19082 Royal Collection Trust. Accessed June 22, 2022. https://www.rct.uk/collection/919082/the-aortic-valve

2. Philippa Roxby. What Leonardo taught us about the heart. BBC Health: Updated June 28, 2014. Accessed June 22, 2022.https://www.bbc.com/news/health-28054468

3. Bagur R, Pibarot P, Otto CM. Importance of the valve durability-life expectancy ratio in selection of a prosthetic aortic valve. Heart. 2017;103(22):1756-1759. Epub 2017 Sep 13. doi:10.1136/heartjnl-2017-312348

4. Thyregod HGH, Ihlemann N, Jørgensen TH, et al. Five-year clinical and echocardiographic outcomes from the Nordic Aortic Valve Intervention (NOTION) randomized clinical trial in lower surgical risk patients. Circulation. 2019;139:2714-2723. doi:10.1161/CIRCULATIONAHA.118.036606

5. Bartus K, Litwinowicz R, Bilewska A, et al. Intermediate-term outcomes after aortic valve replacement with a novel RESILIA™ tissue bioprosthesis. J Thorac Dis. 2019;11(7):3039-3046. doi:10.21037/jtd.2019.07.33

2.3 Stroke Prevention in TAVR—What’s Missing

Problem Presenter: Michael Rinaldi, MD

Statement of the problem or issue

Despite improvements in devices and techniques, while most complications of TAVR have declined, stroke unfortunately remains prevalent, and improvement in stroke event rates has reached a plateau. Contemporary clinical trials and large registries consistently show rates of 1%-2% for major stroke. If minor strokes are included, events which may be equally consequential to patients, then the rates are even higher, particularly when adjudicated by a neurologist. Additionally, virtually all TAVR procedures are associated with magnetic resonance imaging evidence of cerebral infarction despite a lack of acute symptoms, and emerging data suggest these microinfarcts may be associated with progressive cognitive decline. While relatively low in prevalence, given its severe consequences, stroke remains a significant problem in TAVR.

Gaps in knowledge

Since most emboli occur during the TAVR procedure itself, cerebral protection (CEP) devices have been proposed to help mitigate stroke. While numerous CEP devices are under investigation, the Sentinel device is the most extensively studied, it has received FDA approval, and is in current clinical use. Existing data remain controversial though. The Sentinel IDE Trial showed numerically fewer strokes at the 30-day endpoint, but this was not statistically significant. However, a post hoc analysis of strokes within the 72-hour periprocedural window did show statistically fewer events. Several registries suggest fewer event rates with CEP, although an analysis of the TVT registry showed only a trivial reduction in stroke. All registries may be subject to bias and confounding. Thus, use of CEP remains highly variable in clinical practice, with only 5% of institutions in the US using CEP routinely, and no more than one-half using CEP selectively. An ongoing clinical trial, PROTECTED TAVR, should add insights. Yet, if PROTECTED TAVR is negative, how will that change this field? Do we move on to other technologies or would this severely diminish further interest? How positive would PROTECTED TAVR have to be to change CEP usage? Will PROTECTED TAVR have enough statistical power to identify subgroups that do and do not benefit from CEP? How can we better study long-term cognitive effects of “silent emboli,” and their prevention? Are better technologies than Sentinel needed? Is arch manipulation for TAVR deployment causing more harm than benefit? Is radial access required or is large bore femoral access acceptable given its bleeding risks? Is there any role for pharmacology in stroke prevention, for example, with different drug agents or activated clotting time (ACT) targets? Is air embolism a significant contributor to stroke, or is this a red herring distraction?

Possible solutions and future directions

Mechanistically, Sentinel CEP should work, with virtually all baskets retrieving embolic material regardless of estimated surgical risk profile. But it is possible that the filters miss material, or the process of placing filters itself results in cerebral emboli. Other investigational devices attempt to mitigate these potential shortcomings with more complete arch coverage or less manipulation, but whether these different designs will result in meaningful improvements in stroke remains to be studied. Finally, recent data question the role of air embolism generated by TAVR device preparation and the deployment procedure, where embolic protection filters would be less effective, as contributors to stroke. The recently completed PROTECTED TAVR randomized trial of Sentinel CEP should provide critical data that, if positive, may show improved outcomes, or, on the other hand, if negative, might result in reassessment of the entire field of CEP.

IAGS 2022 Session 3: Endovascular Session 1

3.1 Paclitaxel: Friend or Mortal Foe?

Problem Presenter: Jihad A. Mustapha, MD

Statement of the problem or issue

The antimitotic drug paclitaxel is a promising therapy for preventing hyperplasia and cellular proliferation in the treatment of atherosclerotic disease of both superficial femoral arteries (SFA) and popliteal arteries. However, over time, certain misconceptions arose about its safety over the longer term, especially its possible effects on mortality at 5 years.¹ Because of this, the FDA has been cautious in its consideration of paclitaxel-coated balloons for treatment and prevention of restenosis.²

These longer-term safety issues have led to a redirection of interest away from other secondary antiproliferative agents, such as the limus family of drugs, which might be used to improve current treatments below the knee (BTK) and especially with tibial artery atherosclerotic disease. It is unclear whether these other agents would be as safe and effective as paclitaxel. Although we can debate whether paclitaxel itself is associated with increased mortality or not, at least we can agree that paclitaxel is effective. Will we face the same questions 5 years from now with the limus family of agents?

Paclitaxel is one of the more favorable agents when attached to an excipient for transportation into the body and then into the vessel media. However, embolization is still a major issue because just as paclitaxel can be easily attached to an excipient, it can just as easily be detached. The amount of paclitaxel that can be used is limited by the length of the atherosclerotic lesions. This is appropriate for now, but what if drug-coated balloon treatment becomes mainstream therapy? How will we resolve this dose issue? There is also discordance in the concentrations of the drug placed onto current commercially available balloons. There is disagreement on the value of low-dose vs high-dose concentrations. How can we resolve those concerns?

Gaps in knowledge

Previously, the trend in thinking was that tibial arteries are similar to coronary arteries. But let’s stop for a second and think about that: coronary arteries have an inner endothelial layer, surrounded by a media consisting of 3 to 5 layers of smooth muscle cells, and then an adventitia with an outer elastic membrane. However, the tibial arteries are dramatically different from coronary arteries in multiple ways and we should never compare the two. Tibial arteries have dual smooth muscle cell layers. The first is a proliferative-type smooth muscle cell layer and the second is a secretion-type smooth muscle cell layer.

When you see a hyperplastic response to balloon angioplasty in tibial arteries, think of the “beast” of a thick, hyperproliferative dormant layer that is awakened by the significant radial force applied by the balloon. This radial force triggers an over-reactive response to the point of possible complete obliteration of the tibial lumen. This aggressive hyperproliferative response appears to happen more commonly in the distal tibial arteries rather than in the proximal tibial arteries. We don’t yet know why this occurs.

The secretory smooth muscle cells are triggered by unknown factors, many are which are still hypothetical at present. However, diabetes and renal disease seem to be most common factors of the ones known. There is a theory that these 2 conditions, diabetes and renal disease, can lead to formation of calcifications, starting with a phenomenon known as calcium dust phosphate formation. This process can continue until we see the ever-famous medial calcium accumulation. Eventually, this secretory medial layer can transform into osteocytes, with osteophytes and actual bone formation occurring within the medial layer of the vessel. The individual variation in severity of this medial calcification seems to be consistent with the chronicity of the other comorbidities, but as the process unfolds it leads ultimately to the lack of any utility from paclitaxel treatment at this point. It was demonstrated in the DEBELLUM study that paclitaxel cannot penetrate this type of tissue.^3,4

Possible solutions and future directions

The reality is this: if you treat these vessels every day, you quickly learn that plain old balloon angioplasty alone is more detrimental than helpful in the treatment of these peripheral vessels. On the other hand, atherectomy of various types may alter the medial wall barrier and possibly provide for better uptake of paclitaxel into the newly fractured channels leading into the subadventitial areas.

A method is needed for circumferential barrier penetration with drug delivery on both sides of the barrier wall: this would lead to inhibition of the proliferative smooth muscle cells of the media and at the same time inhibit the signals for hyperplasia that are coming from the subadventitia. Currently there are devices in development and under study that show promise in enhancing delivery of the paclitaxel (or other) drug. If calcium is not present in the media, then a 1:1 ratio of balloon-to-artery will provide the best preparation for these vessels prior to drug-eluting balloon delivery.

References

1. Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Karnabatidis D. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2018;7(24):e011245. doi:10.1161/JAHA.118.011245

2. Farb A, Malone M, Maisel WH. Drug-coated devices for peripheral arterial disease. N Engl J Med. 2021;384(2):99-101. doi:10.1056/NEJMp2031360

3. Fanelli F, Cannavale A, Corona M, Lucatelli P, Wlderk A, Salvatori FM. The “DEBELLUM”— lower limb multilevel treatment with drug eluting balloon—randomized trial: 1-year results. J Cardiovasc Surg (Torino). 2014;55(2):207-216.

4. Fanelli F, Cannavale A, Gazzetti M, et al. Calcium burden assessment and impact on drug-eluting balloons in peripheral arterial disease. Cardiovasc Intervent Radiol. 2014;37(4):898-907. doi:10.1007/s00270-014-0904-3

3.2 Aortic Frontiers: Will Branched Arch and Thoraco-abdominal Devices Outperform Surgery?

Problem Presenter: Sigrid Nikol, MD

Statement of the problem or issue

The first endovascular aortic stent-graft was implanted by Nikolay Volodos in Khrakov, Ukraine, on May 4, 1984.¹ However, this achievement did not receive much attention outside of Eastern Europe. It was not until 1990, when the first abdominal aortic endoprosthesis was implanted by Juan Parodi and Julio Palmaz in Buenos Aires, Argentina, and 1992 when endoprostheses were implanted into the thoracic aorta by Michael Dake and into the abdominal aorta by Frank Veith in the USA, that transluminal endovascular interventions began to receive significant attention.^2-4 Standard endovascular aortic repair (EVAR) for abdominal aortic aneuryms (AAA), and thoracic endovascular aortic repair (TEVAR) for thoracic aortic aneurysms (TAA), have largely replaced open surgical repair, with lower rates of mortality, morbidity, and paraplegia. In addition, procedural times and in-hospital stays are shorter. Yet despite these gains, aneurysms of the aortic arch and thoracoabdominal aneurysms remain a challenge. With open surgery approaches, high rates of strokes and paraplegias are continuing problems in the management of these complex aortic aneurysm repairs. Also, the technique of chimney graft repair, requiring brachial access and manipulation of the arch, can have high stroke rates. Newer endovascular devices with branches and fenestrations have been developed to try to circumvent these problems.

Gaps in knowledge

A major issue is the unavailability of many new devices with fenestrations (FEVAR) and branches (BEVAR) in several countries, including the USA. Whereas some of the aortic endoprostheses are off-the-shelf devices that have received CE-marking and regulatory approval, others have to be produced as custom-made devices (CMDs) without such approval possible. Hence, the interventionalist carries the responsibility for proper device use, as stated in the accompanying letters of the manufacturing companies. Despite these limitations, such CMDs are used in Australia and Europe, with liability covered by institutions and insurance carriers.

One major consequence of this lack of availability of either approved off-the-shelf or CMD aortic endoprostheses is the difficulty in both planning such procedures using special computer programs as well as the often very demanding implantation into challenging anatomies. Another consequence of having few devices, less device-specific training, and reduced skills is that open surgery may also be needed more frequently as a result. Also, in the absence of having complex CMD endoprostheses, there are risks to “pushing the limits” using standard devices, particularly regarding instructions for use (IFU) for suitable landing zones, irregular aneurysm necks, and neck angles. These may not appear as problems immediately following the implantation of EVARs and TEVARs, but over time and with progression of disease, patients may require subsequent even more demanding procedures with proximal and distal extensions.

Possible solutions and future directions

In Europe and Australia, thoraco-abdominal FEVAR and BEVAR by now have become routine, and long-term data are favorable. Experience with FEVAR and BEVAR in the aortic arch is rapidly increasing, yet these are still lacking large series and long-term data. All these complex procedures work best in dedicated aorta centers. Besides lack of expertise, there also is a large selection of necessary additional materials, supplies, and equipment that may not be readily available in smaller centers whenever procedural challenges occur.

CMDs often require long production times and often have to be shipped around the world, which may take up to 2-3 months. With very large aneurysms at high risk of rupture, and in symptomatic patients and emergencies with actual ruptures, more rapid solutions are needed. A larger variety of approved off-the-shelf devices would help. Also, physician-modified devices in the hands of experienced interventionalists familiar with planning tools have become a more frequent alternative to CMDs, and not only because they are rapidly available, but also may be cost saving. Liability, of course, is with the physician, who also requires extra knowledge and training. Lower-profile devices are needed for branched and fenestrated endoprostheses, since narrow and calcified access arteries may be problematic in complex procedures, especially in women. Lower-profile devices in combination with large-bore closure systems will facilitate percutaneous approaches while avoiding surgical cut-downs. These improvements in closure devices are still desired. Technical innovations such as fusion imaging for the cannulation of target arteries, which reduces both procedure times and radiation exposure, are very helpful. The development of robotic techniques could further decrease radiation doses.

References

1. Criado FJ. Nicholay Volodos and the origins of endovascular grafts. J Endovasc Ther. 2012;19(4):568-569. doi:10.1583/12-3972L.1

2. Parodi JC, Palmaz JC, Barone HD. Transfemoral intraluminal graft implantation for abdominal aortic aneurysms. Ann Vasc Surg. 1991;5(6):491-499. doi:10.1007/BF02015271

3. Mitchell RS, Dake MD, Sembra CP, et al. Endovascular stent-graft repair of thoracic aortic aneurysms. J Thorac Cardiovasc Surg. 1996;111(5):1054-1062. doi:10.1016/s0022-5223(96)70382-3

4. Marin ML, Veith FJ, Cynamon J, et al. Initial experience with transluminally placed endovascular grafts for the treatment of complex vascular lesions. Ann Surg. 1995;222(4):449-465; discussion 465-469. doi:10.1097/00000658-199522240-00004

3.3 Carotid Artery Disease: CEA, CAS, TCAR, or Just Pills?

Problem presenter: Tyrone J. Collins, MD

Statement of the problem or issue

Carotid arterial disease is usually caused by atherosclerosis and it results in narrowing of the arteries in the neck that supply blood to the brain. Unfortunately, carotid disease often does not cause symptoms until the narrowing becomes severe and/or a thromboembolic event occurs. There are several diagnostic tests that can be performed to confirm the diagnosis. Then, the real dilemma becomes: what is the best treatment option. A surgical procedure, carotid endarterectomy (CEA), is the oldest invasive treatment available, and it is relatively safe when performed by experienced surgeons. However, some patients are at high or even prohibitive risk for this surgery. Percutaneous carotid artery stenting (CAS) and transcarotid artery revascularization (TCAR) are alternatives to CEA. Additionally, over the years since the advent of CEA therapy, there have been advances in pharmacology that have expanded medical treatment options, and these possibly may alter the need for invasive approaches.

Gaps in knowledge

What is the most appropriate treatment for each individual patient with carotid disease has not been resolved. Risk stratification for carotid revascularization is at the forefront of the decision-making process for selecting treatment. There is no universally accepted risk stratification schema. Interestingly, the technical abilities required to perform a safe procedure are often overlooked. Data reveal the decreasing incidence of complications over the years as operator experience increases and advances in technology provide operators with better and safer equipment. Trials have been conducted yielding varying results. Comparisons of therapies have been interpreted with divergent conclusions. The role of aggressive medical therapy in lieu of invasive procedures has not been fully evaluated, and yet may be the only treatment necessary in asymptomatic patients despite the degree of carotid stenosis.

Possible solutions and future directions

Limited insurance coverage for CAS began in 2001 for patients who could participate in investigational device exemption (IDE) trials. Medicare (CMS) still does not cover CAS unless patients are symptomatic, are at high surgical risk, and have a high degree of stenosis. Despite numerous registries and randomized trials that have demonstrated its clinical benefit, CAS remains one of the most political issues in medicine. We must push to allow this percutaneous option for our patients and at the same time ensure that procedures are performed by the appropriate physicians. Training in fellowship programs should be comprehensive and provide a level of expertise that can be documented, if a trainee plans to perform these procedures after graduation. We anxiously await the results of the ongoing CREST II trial and encourage industry to continue to explore newer technologies.

IAGS 2022 Session 4: Coronary Session 2—STEMI

4.1 COMPLETE Revascularization Following STEMI: Not Whether, When

Problem Presenter: Janarthanan Sathananthan, MD

Statement of the problem or issue

Patients presenting with ST–segment-elevation myocardial infarction (STEMI) often have multivessel coronary artery disease. The large multicenter randomized COMPLETE trial enrolled patients with STEMI who underwent culprit-lesion PCI, and had at least 1 additional angiographically significant nonculprit lesion (≥70% diameter stenosis by visual estimation in a vessel with diameter of ≥2.5 mm).¹ Staged nonculprit lesion PCI with the goal of complete revascularization, which was achieved in >90% of patients, resulted in significant reductions of the individual primary outcomes of cardiovascular (CV) death, or new MI, as well as in the composite outcome of CV death, new MI, or ischemia-driven revascularization (IDR), when compared with culprit–lesion-only PCI. (8.9% vs 16.7%; P<.001 for the composite outcome). Current guidelines now recommend routine revascularization for nonculprit lesions in patients presenting with STEMI. In the COMPLETE study, nonculprit revascularization could be performed either during index hospitalization or within several weeks after discharge. A COMPLETE trial substudy demonstrated that staged nonculprit lesion PCI performed either early, that is, during the index hospitalization, or alternatively several weeks after discharge, led to a similar reduction in the composite outcome of CV death or MI, compared with culprit–lesion-only PCI.² The benefit of nonculprit-lesion PCI emerges mainly over the long term, generally years.²

Gaps in knowledge

While it has been shown that revascularization of nonculprit lesions in STEMI patients with multivessel disease is beneficial, it is unknown exactly which patients and w­hich nonculprit lesions benefit most from inpatient revascularization during the index ­hospitalization.

Possible solutions and future directions

Further studies are needed to establish how long non-culprit lesion revascularization can be safely delayed after an index STEMI presentation, while still yielding long-term clinical benefit. Understanding which factors favor inpatient complete revascularization compared to later revascularization will also be of great importance.

References

1. Mehta SR, Wood DA, Storey RF, et al. Complete revascularization with multivessel PCI for myocardial infarction. N Engl J Med. 2019;381(25):1411-1421. doi:10.1056/NEJMoa1907775

2. Wood D, Cairns J, Wang J, et al. Timing of staged nonculprit artery revascularization in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2019;74(22):2713-2723. doi:10.1016/j.jacc.2019.09.051

4.2 Therapies to Minimize Myocardial Injury and to Promote ­Myocardial Recovery Following STEMI

Problem Presenter: Richard W. Smalling, MD, PhD

Statement of the problem or issue

Despite tremendous efforts over the past 40+ years, 30-day mortality in patients with ST–segment-elevation myocardial infarction (STEMI) remains ≈10%, and late mortality is significantly higher still. This makes STEMI a leading cause of death in western civilization. STEMI most often results from rupture of a vulnerable atherosclerotic plaque in a major epicardial coronary artery, with intraluminal thrombus formation leading to occlusion of this infarct-related artery (IRA). Occlusion leads to necrosis of myocardium in the IRA distribution zone. Animal and human studies show that IRA reperfusion must occur within 2 hours after onset of symptoms for significant myocardial salvage to occur. Unfortunately, after onset of symptoms, many patients delay contacting emergency medical system (EMS) providers until more than 2 hours of time has passed. Therefore, quickly initiating IRA reperfusion with fibrinolysis in the field or pre-transfer could achieve reperfusion sooner, with significant decreases in mortality, provided the risks of fibrinolysis are small. Previous randomized prehospital fibrinolytic trials excluded high-risk patients (cardiogenic shock or brief cardiac arrest) and they used higher doses of lytics than necessary. This resulted in worse outcomes compared with primary PCI (pPCI) and so enthusiasm for fibrinolysis diminished. We have learned that merely reducing door-to-balloon times in STEMI patients treated with pPCI alone has failed to demonstrate improved outcomes over the past 10 years. The major reason for the persistently high mortality in STEMI patients seems to be the fact that IRA reperfusion in the current system typically occurs beyond the 90- to 120-minute window for significant myocardial salvage. Also, paradoxically, restoration of oxygenated blood flow into the ischemic myocardium can lead to additional myocardial necrosis, a process termed reperfusion injury. Currently, there are no definitive effective treatments for prevention of reperfusion injury.

Gaps in knowledge

It is very likely that “newer” strategies to achieve prompt IRA reperfusion would markedly improve outcomes in STEMI patients. In addition to this, a handful of therapies have shown some promise of eliminating or dramatically reducing the additional myocardial damage from reperfusion injury. In order to fully investigate effectiveness of any new therapies, it will be essential to include high-risk patients (brief cardiac arrest or cardiogenic shock) in clinical trials. It is now clear that these high-risk patients are the ones most likely to benefit from aggressive treatment.¹

Possible solutions and future directions:

Nonrandomized studies of half-dose fibrinolysis given with aspirin, glycoprotein IIb/IIIa inhibitors, and low-dose heparin administered pre-hospital (or pre-transfer from spoke hospitals) prior to PCI have demonstrated dramatic reductions in mortality without a bleeding or stroke penalty compared with pPCI alone. But it will be necessary to perform RCTs to demonstrate definitively the benefit of half-dose fibrinolytic administration followed by urgent PCI. We also know from animal experiments, observational studies, and limited RCTs that unloading the left ventricle (LV) with an intra-aortic balloon pump (IABP) or transvascular LVAD such as Impella prior to IRA reperfusion can significantly reduce late mortality and heart failure/shock (Figure 1).^2,3 The benefit of unloading may be related to reduction in reperfusion injury.

In conclusion, we must perform adequately powered randomized trials including both high-risk and intermediate-risk STEMI patients to prove the benefits of accelerated reperfusion and LV unloading for infarct salvage improved recovery.

References

1. Herrmann HC, Lu J, Brodie BR, et al. Benefit of facilitated percutaneous coronary intervention in high-risk ST-segment elevation myocardial infarction patients presenting to nonpercutaneous coronary intervention hospitals. JACC Cardiovasc Interv. 2009;2(10):917-924. doi:10.1016/j.jcin.2009.06.018

2. LeDoux JF, Tamareille S, Felli PR, Amirian J, Smalling RW. Left ventricular unloading with intra-aortic counterpulsation prior to reperfusion reduces myocardial release of endothelin-1 and decreases infarction size in a porcine ischemia-reperfusion model. Catheter Cardiovasc Interv. 2008;72(4):513-521. doi:10.1002/ccd.21698

3. O’Neill WW, Schreiber T, Wohns DH, et al. The current use of Impella 2.5 in acute myocardial infarction complicated by cardiogenic shock: results from the USpella registry. J Interv Cardiol. 2014;27(1):1-11. doi:10.1111/joic.12080

4.3 Interventional Pharmacology: Data-Driven Best Practices

Problem Presenter: E. Magnus Ohman, MD

Statement of the problem or issue

From the first percutaneous coronary intervention (PCI) done by Andreas Gruentzig in the 1970s, antithrombotic therapy has been used, usually a combination of antiplatelet and anticoagulation therapy. Aspirin (ASA) and heparin were used during the early years of balloon angioplasty, typically in higher doses than currently in use now: ASA 325-500 mg and heparin 10,000 IU. Beginning in the 1980s, it became possible to monitor levels of anticoagulation with ACT during PCI in the cath lab and then afterward at the bedside. The level of ACT attained was adopted from cardiopulmonary bypass surgery, where “adequate ACTs” had been judged to be 300-500 seconds. Subsequent work noted higher bleeding rates with ACT >350 seconds, and heparin doses were adjusted to achieve lower ACTs closer to 250 seconds. Heparin typically was given in repeated bolus doses to arrive at this ACT level during a PCI procedure (about every 30 minutes) due to the short half-life and variable therapeutic response. More recently, intravenous bivalirudin, a direct thrombin inhibitor, has used the same level of ACT to define an “adequate level” of anticoagulation. Bivalirudin is given in a continuous infusion after an initial bolus dose. This approach does not require repeated ACT measurements during the PCI procedure. There have been very few RCTs comparing heparin and bivalirudin, so the majority of catheterization laboratories use what is customary to them, as either anticoagulant appears to be safe and effective.

A major breakthrough in antiplatelet therapy came in the 1990s when agents became available that could block the final common pathway of platelet activation, the glycoprotein (GP) IIb/IIIa receptor. The first such agent was abciximab, an antibody to the glycoprotein receptor, which clinically reduced adverse ischemic outcomes in PCI, but also produced higher bleeding rates. Eptifibatide and tirofiban, both of which are reversible GP IIb/IIIa inhibitors, were later introduced. In aggregate, all of these agents reduced thrombotic and ischemic events after PCI in both stable and ACS patients (including STEMI), as proven in RCTs. Observational studies during this period found that heparin dosing could be reduced to achieve ACTs just above 200 seconds, and this was associated with less bleeding but still retained the anti-ischemic benefits.

With the introduction of bare-metal stents in the late 1990s, it became clear that although GP IIb/IIIa receptor inhibitors were very effective in reducing acute stent thrombosis, patients remained vulnerable to later stent thrombosis, particularly with drug-eluting stents. Observational studies suggested that oral clopidogrel (an irreversible inhibitor of the platelet ADP surface receptor) had important antiplatelet effects that continued over the long term, especially when combined with ASA. Subsequent RCTs found oral clopidogrel loading doses of 600 mg were required prior to the PCI procedure (with ASA and heparin administered as usual). Large RCTs with other ADP receptor inhibitors, oral prasugrel (irreversible) and oral ticagrelor (reversible), provided both short-term and long-term anti-ischemic effects that were superior to clopidogrel. However, minor increases in bleeding were noted with both of these agents. The majority of PCI procedures (elective, urgent, and emergency) are now performed with one of these oral agents along with ASA and heparin. There have been no adequately powered comparative studies with the more potent agents (prasugrel and ticagrelor) that differentiate a clear superiority between these agents.

The oral ADP antagonists take on average about 60-120 minutes to achieve therapeutic blood levels, which is reasonable for most patients, even many acute coronary syndrome (ACS) patients. However, this time delay is inadequate for STEMI patients undergoing primary PCI, or in other cases when patents are given oral loading doses on the catherization table for an ad hoc PCI procedure, where immediate ADP antagonism is required. However, as an alternative, the intravenous ADP antagonist cangrelor (given as a bolus and infusion for up to 4 hours) has been found to be effective in reducing ischemic events, including stent thrombosis, in the first 48 hours after PCI when compared with oral clopidogrel, ASA and either heparin or bivalirudin. There is limited experience combining cangrelor with intravenous GP IIb/IIIa inhibitors.

Gaps in knowledge

The optimal combination of anti-platelet and anticoagulant agents is largely unknown due to the historical development of these therapies in PCI. There are 18 possible permutations of existing agents. Only about half of these combinations have been tested in RCTs during PCI. Additionally, the majority of these trials have been conducted in ACS patients undergoing PCI, and very few have included large populations of PCI patients with either stable ischemic heart disease or STEMI. The majority of PCI operators and cardiac catherization laboratories use therapies that they have worked with for a while and are comfortable with, suggesting there is no real consensus on what to use outside of ASA. There have been insufficient direct head-to-head RCTs of newer agents, and most studies explore an experimental therapy added on top of standard existing therapies, rather than exploring a complete replacement of existing therapies.

In the early phase of diagnostic angiography in the 1970s, intravenous heparin was routinely used for angiography when it was given during brachial cut-down procedures to prevent brachial artery thrombosis. This habit was carried over to when angiography was performed using the femoral access. This approach was largely dropped in the early 1990s. Administering intravenous heparin during diagnostic angiography has seen a resurgence with the use of radial access in the early 2000s as radial artery thrombosis was observed. As ad hoc PCI is now increasingly performed after radial cardiac catherization the majority of patients receive 5000 units of intravenous heparin even before the PCI is contemplated. This has led to a resurgence of heparin for all types of PCI irrespective of the indication. Little is known about alternative anticoagulation approaches for radial PCI.

The majority of PCI antithrombotic trials were carried out in ACS populations, and very few trials have addressed optimal antithrombotic therapy for non-ACS patients undergoing elective PCI. Fortunately, ischemic events are very rare, as are bleeding events in stable, elective PCI patients. The one exception would be patients undergoing high-risk PCI procedures (low ejection fraction, multivessel PCI, or atherectomy) where adverse events such as thrombosis and periprocedural MI remain high. No RCTs have addressed the most appropriate antithrombotic therapy in this population. The majority of PCI procedures for chronic total occlusion (CTO) use heparin as anticoagulation due to the ability to reverse the anticoagulation if coronary perforation is observed. Similarly, short-acting intravenous ADP antagonists are preferred since the biological effect is very brief (15 minutes) after the infusion is turned off. This approach has not been subjected to a RCT.

Possible solutions and future directions

As is evident from the above discussion, the majority of changes in antithrombotic therapies have come from careful clinical observations, similar to the evolution of antithrombotic therapies in bypass surgery. RCTs have explored use of the newer agents, but these trials have seldom included head-to-head comparisons. New antithrombotic therapies may be developed in the future and the challenge will be how these should be tested as there is no clear standard of care for antithrombotic therapy in PCI. ASA is a given, but beyond that there are many possibilities that are unlikely to be included in any future RCTs of new agents.

One solution, which has largely been adopted already, is to use more potent antiplatelet therapies for the more complex and high-risk PCI patients. This appears logical, but no observational study has addressed this approach. To move the field of antithrombotic therapy in PCI forward, we should ideally collect careful clinical and angiographic data on the majority of patients that undergo PCI procedures. Some national registries in Sweden, the United Kingdom, and the USA are poised to do so, but these may lack the fidelity to collect the important angiographic data needed to best risk-stratify these patients.

IAGS 2022 Session 5: Structural Session 2—Mitral and Tricuspid Valve

5.1  Interventional vs Surgical Mitral Repair: Are Valve Centers of Excellence Needed?

Problem Presenter: Molly Szerlip, MD

Statement of problem or issue

Approaches to mitral valve disease are undergoing re-evaluation as both technologies and clinical experiences evolve.

Gaps in knowledge

There are 3 major gap areas:

1. Is valve durability better with one approach over the other?

2. Do Centers of Excellence permit better patient selection—resulting in better outcomes?

3. Would Centers of Excellence limit access to care?

Do patients really care about “valve durability?” The patients’ priorities are: (1) recovery time and (2) getting back to their lives sooner. If a percutaneous approach fails then the patient faces having to undergo a surgical mitral valve replacement and consequent anticoagulation. Also, a large meta-analysis showed similar mortality rates but higher rates of residual regurgitation and reoperation in percutaneous approach patients.¹

Centers of Excellence that offer both surgery and percutaneous approaches have greater transparency with their procedure outcomes, and more often engage in public reporting initiatives.² But since they are fewer in number and farther from patients, do these Centers of Excellence unnecessarily limit or restrict access to therapies?

Possible solutions and future directions

Mitral valve disease is not a single entity, and subsets may each require different approaches. One paramount consideration is public reporting of outcome metrics. This will help ensure program integrity. Multihospital organizations will need to develop regionalization and true systems of care, with resource-sharing and referral networks.

References

1. Oh NA, Kampaktsis PN, Gallo M, et al. An updated meta-analysis of MitraClip versus surgery for mitral regurgitation. Ann Cardiothorac Surg. 2021;10(1):1-14. doi:10.21037/acs-2020-mv-24

2. Nishimura RA, O’Gara PT, Bavaria JE, et al. 2019 AATS/ACC/ASE/SCAI/STS Expert Consensus Systems of Care Document: a proposal to optimize care for patients with valvular heart disease: a joint report of the American Association for Thoracic Surgery, American College of Cardiology, American Society of Echocardiography, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2019;73(20):2609-2635. doi:10.1016/j.jacc.2018.10.007

5.2. TMVR: Programmatic Challenges and Technology Needed to Match Surgical Outcomes

Problem Presenter: Adam Greenbaum, MD

Statement of the problem or issue

Early intervention improves survival with surgical mitral valve replacement (SMVR) for primary degenerative mitral regurgitation (MR). Survival benefit with surgery for secondary MR is less clear. Higher recurrences of MR after repair compared to lower recurrences after replacement has caused a shift to more surgical replacements (Figure 1).^1,2

Gaps in knowledge

Issues with TMVR can be divided into 2 types: (1) programmatic; and (2) technical.

Programmatic issues

The Edwards Sapien 3 valve is the only valve available for TMVR (Figure 2).

A major issue in clinical testing of the TMVR procedure is low volume per center, especially when compared with transcatheter edge-to-edge repair (TEER).³ All other transcatheter heart valves (THVs) for TMVR are investigational. Furthermore, there are few investigational centers for the new valves, and there is very slow enrollment at investigating sites.

Technical issues

The technical challenges with TMVR are: (1) valve alignment; and (2) left ventricular outflow tract (LVOT) obstruction. First, valve alignment can be difficult due to the transseptal approach. Poor alignment leads to paravalvular leak (Figure 3).

Another technical challenge is LVOT obstruction. The reported incidence is approximately 2%. There are both fixed and dynamic causes of obstruction. Prevention is the only treatment at present.

Possible solutions and future directions

For valve alignment, possible solutions include alternative approaches, possibly even transapical. Other maneuvers include “push-pull” traction on the wire and catheter, and posterior guide deflection. The valve skirt size could be increased. Wire exteriorization via the aorta or para-apical routes may be possible. For LVOT obstruction, methods that may help are: (1) techniques to “re-orient” the transcatheter valve; (2) methods to remove the anterior leaflet via transatrial resection, LAMPOON, or BATMAN; and (3) methods to increase LVOT diameter.^4-11

The final and ultimate questions are these: Do we need:

• “More data?”

• Real-world registries or prospective trials?

• Better tools?

• To understand which patients are likely to benefit—ie, better and more focused patient selection?

References

1. Suri RM, Vanoverschelde JL, Grigioni F, et al. Association between early surgical intervention vs watchful waiting and outcomes for mitral regurgitation due to flail mitral valve leaflets. JAMA. 2013;310(6):609-616. doi:10.1001/jama.2013.8643

2. Acker MA, Parides MK, Perrault LP, et al. Mitral-valve repair versus replacement for severe ischemic mitral regurgitation. N Engl J Med. 2014;370(1):23-32. Epub 2013 Nov 18. doi:10.1056/NEJMoa1312808

3. Mack M, Carroll JD, Thourani V, et al. Transcatheter mitral valve therapy in the United States: a report from the STS-ACC TVT Registry. J Am Coll Cardiol. 2021;78(23):2326-2353. Epub 2021 Oct 25. doi:10.1016/j.jacc.2021.07.058

4. Babaliaros V, Greenbaum AB, Kamioka N, et al. Bedside modification of delivery system for transcatheter transseptal mitral replacement with POULEZ system and SAPIEN-3 valve. JACC Cardiovasc Interv. 2018;11(12):1207-1209. doi:10.1016/j.jcin.2018.03.015

5. Rahhab Z, Ren B, de Jaegere PPT, Van Mieghem NMDA. Kissing balloon technique to secure the neo-left ventricular outflow tract in transcatheter mitral valve implantation. Eur Heart J. 2018;39(23):2220. doi:10.1093/eurheartj/ehy11

6. Greenbaum AB, Lisko JC, Gleason PT, et al. Annular-to-apical “emory angle” to ensure coaxial mitral implantation of the SAPIEN 3 valve. JACC Cardiovasc Interv. 2020;13(20):2447-2450. doi:10.1016/j.jcin.2020.07.024

7. Babaliaros VC, Greenbaum AB, Khan JM, et al. Intentional percutaneous laceration of the anterior mitral leaflet to prevent outflow obstruction during transcatheter mitral valve replacement: first-in-human experience. JACC Cardiovasc Interv. 2017;10(8):798-809. doi:10.1016/j.jcin.2017.01.035

8. Case BC, Khan JM, Satler LF, et al. Tip-to-base LAMPOON to prevent left ventricular outflow tract obstruction in valve-in-valve transcatheter mitral valve replacement. JACC Cardiovasc Interv. 2020;13(9):1126-1128. Epub 2020 Apr 15. doi:10.1016/j.jcin.2020.01.235

9. Helmy T, Hui DS, Smart S, Lim MJ, Lee R. Balloon assisted translocation of the mitral anterior leaflet to prevent left ventricular outflow obstruction (BATMAN): a novel technique for patients undergoing transcatheter mitral valve replacement. Catheter Cardiovasc Interv. 2020;95(4):840-848. Epub 2019 Sep 13. doi:10.1002/ccd.28496

10. Wang DD, Guerrero M, Eng MH, et al. Alcohol septal ablation to prevent left ventricular outflow tract obstruction during transcatheter mitral valve replacement: first-in-man study. JACC Cardiovasc Interv. 2019;12(13):1268-1279. doi:10.1016/j.jcin.2019.02.034

11. Khan JM, Bruce CG, Greenbaum AB, et al. Transcatheter myotomy to relieve left ventricular outflow tract obstruction: the septal scoring along the midline endocardium procedure in animals. Circ Cardiovasc Interv. 2022;15(6):e011686. Epub 2022 Apr 5. doi:10.1161/CIRCINTERVENTIONS.121.011686

5.3 Tricuspid Valve Interventions: Repair or Replace

Problem Presenter: William O’Neill, MD

Statement of the problem or issue

The tricuspid valve (TV) is a monster valve, and by this I mean in terms of what happens when people have longstanding annular dilatation, causing the right atrium and the annulus both to enlarge dramatically. When this happens, leaflet edge technologies are likely going to play only a minor role. There are 3 leaflets to the TV: the anterior leaflet, the septal leaflet, and the posterior leaflet. One thing that is very common and underappreciated is a pacemaker-induced TV dysfunction. All of us dealing with TR know what I mean, and unfortunately electrophysiologists almost never see the problem: the device lead fixes or plasters the septal leaflet down against the wall, or in some cases there are actually redundant leads across the TV, causing massive tricuspid regurgitation (TR). In the pacemaker clinic the device thresholds are okay, and that’s fine, but nobody notices the patient’s legs are swelling up. A lot of this likely will resolve with the advent of leadless pacemakers, but unfortunately, TR is very difficult to treat because the patients really don’t become symptomatic for months to a year. So, months later they go back to their primary care doctor with swollen legs, and their primary doctor will give them diuretics, etc., and never send any feedback to the electrophysiologist that the lead is causing massive TR. By the time it’s recognized the lead have already fixed or plastered the leaflet down. Another common situation we deal with as the population ages will be atrial fibrillation, so MR/TR. Those patients are going to have wide open TR and the biggest problem with TR is that it is a mortality issue.¹

In addition, in the structural heart disease environment there’s a problem with our TAVR patients. We have learned that TR in these patients impacts their survival, perhaps even more so than the aortic valve problem.²

Gaps in knowledge

Almost everything we confront in the TV space is a knowledge gap: historically it has been the “forgotten valve.”

Possible solutions and future directions

Replacement of the TV rather than repair is likely where we are headed over the next 10 years. For example, Edwards has produced the Evoque valve, which has recently reported favorable clinical results.^3,4 This device is shown in Figure 1.

In addition, there are other new technologies under investigation; some of them are focused on leaflet repair rather than TV replacement. For example, there is a European registry of the Edwards Pascal tricuspid clip (NCT05328284), and a clinical evaluation of the Abbott tricuspid clip system has recently been published.⁵ A comprehensive review published in 2020 outlined some of the emerging technologies for the TV (Figure 2).⁶ It appears that the once “forgotten valve” has been rediscovered.

References

1. Nath J, Foster E, Heidenreich PA. Impact of tricuspid regurgitation on long-term survival. J Am Coll Cardiol. 2004;43:405-409. doi:10.1016/j.jacc.2003.09.036

2. Lindman BR, Maniar HS, Jaber WA, et al. Effect of tricuspid regurgitation and the right heart on survival after transcatheter aortic valve replacement: insights from the placement of aortic transcatheter valves II inoperable cohort. Circ Cardiovasc Interv. 2015;8(4):10.1161/CIRCINTERVENTIONS.114.002073 e002073. doi:10.1161/CIRCINTERVENTIONS.114.002073

3. Webb JG, Chuang AM, Meier D, et al. Transcatheter tricuspid valve replacement with the EVOQUE system: 1-year outcomes of a multicenter, first-in-human experience. JACC Cardiovasc Interv. 2022;15(5):481-491. doi:10.1016/j.jcin.2022.01.280

4. Kodali S, Hahn RT, George I, et al. Transfemoral tricuspid valve replacement in patients with tricuspid regurgitation: TRISCEND study 30-day results. JACC Cardiovasc Interv. 2022;15(5):471-480. doi:10.1016/j.jcin.2022.01.016

5. Lurz P, Stephan von Bardeleben R, Weber M, et al. Transcatheter edge-to-edge repair for treatment of tricuspid regurgitation. J Am Coll Cardiol. 2021;77(3):229-239. doi:10.1016/j.jacc.2020.11.038

6. Chung CJ, George I. Emerging transcatheter therapies for tricuspid valve disease. JTCVS Open. 2020;2:14-19. doi:10.1016/j.xjon.2020.04.003

IAGS 2022 Session 6: Structural Session 3—Atrial

6.1. LAA Occlusion—Will the Latest Tools and Technologies Help Us Overcome the Barriers?

Problem Presenter: Michael Rinaldi, MD

Statement of the problem or issue

Transcatheter left atrial appendage (LAA) occlusion as a field has matured over the past decade, with clinical trials and registries like PROTECT-AF, PREVAIL, PRAGUE-17, PINNACLE-FLX, and the Amulet IDE study showing progressively improving safety and efficacy profiles that approach or exceed oral anticoagulation. Yet, current LAA occlusion technology is not perfect, with persistent leak rates, rare but persistent device-associated thrombus (DAT), and not all LAA anatomies are favorable for device implant. It has become clear that device leaks, regardless of size, are associated with less effective protection from stroke, and, while it remains unclear if this is confounded or causal, the field now acknowledges that complete elimination of leak is the goal. Additionally, now that even small leaks are thought to be significant, methods for detecting and measuring leaks, including the more sensitive computed tomography angiography (CTA), have not been standardized. Questions remain about comparing leaks between different device designs, including plugs and lobe-with-disc configurations. Additionally, the optimal antiplatelet and anticoagulant (AC) regimen remains unclear, and may not be uniform for all patients. Post implant, oral AC use reduces DAT, but many patients have relative or absolute contraindications to oral AC. Given the results of the ACTIVE-W trial showing no difference in bleeding between DAPT and oral AC, much controversy remains regarding the roll of DAPT in high bleeding risk patients. Recent data suggest half-dose apixaban monotherapy is associated with lower bleeding and DAT rates, although this remains an off-label use. Finally, antithrombotic coating of LAA devices has been proposed as another strategy to reduce DAT, and this is under development and investigation.

Gaps in knowledge

Given that leaks of all sizes are associated with higher stroke rates, should we be plugging or coiling leaks when they are observed, and how would we study this? Will steerable guides improve outcomes? Are our current devices good enough, or do we need transformational technology both to address anatomic challenges and to abolish leaks? Are antithrombotic coatings a game changer or a gimmick? How do we study this? How do we figure out the optimal postimplant pharmacologic regimen? Can intracardiac echocardiography (ICE) for precise ­device placement and confirming absence of leak be the future, or will this negatively impact ­implant quality? Does 4-dimensional (4D)-ICE change the calculus?

Possible solutions and future directions

The CHAMPION-AF and CATALYST clinical trials are randomizing Watchman-FLX and Amulet devices, respectively, with non-vitamin K oral anticoagulants (NOAC). These 2 trials will answer many important questions in the field of LAA occlusion, including whether LAA closure will become a first-line option in atrial fibrillation (AF)-related stroke prevention. LAAOS-3, an RCT of surgical LAA closure, showed incremental reduction in strokes even though most patients continued oral AC, perhaps suggesting a synergistic effect. A LAAOS-4 trial has been proposed to study LAA occlusion using Watchman-FLX with or without oral AC, to further test this hypothesis. Regardless, for high bleeding risk patients, the field desperately needs more data on optimal antiplatelet and anticoagulant regimens post implant. Antithrombotic device coatings may change this, and therefore it may be prudent to wait on more definitive clinical trials until after completion of current device iteration. Exciting new transformational LAA occlusion technology has been proposed, which might reduce the device “footprint,” resulting in a nothing-left-behind scenario. These disruptive technologies may change the field, but they will require further study. ­Finally, procedural evolution to a less invasive procedure not using general anesthesia, with ICE guidance instead of transesophageal echocardiography (TEE), is becoming more common in clinical practice. Limitations in visualization with currently available 2-dimensional ICE technology risks compromising procedural quality with more residual device leaks. Next-generation 4D-ICE has imaging quality on par with TEE and may dramatically narrow the trade-offs, but will require operators to become skilled in procedural image guidance.

6.2. PFO Closure: What Goes Around Comes Around?

Problem Presenter: Victor Lucas, MD

Statement of the problem or issue

Nonsurgical percutaneous closure of PFOs and ASDs dates from the invention of the King-Mills device used first experimentally in dogs in 1972, then with the first human implant performed in 1975. This was a clamshell-umbrella device that was bulky and very challenging. Since that time there have been other devices developed, and device manufacturers continue to work on these although it is not a high priority area. Some of the problems associated with these devices and the implantation procedure are listed in Table 1.

Gaps in Knowledge

In addition to finding solutions to the problems listed in Table 1, the major gaps in our knowledge base are: (1) finding the “right” size and shape for a permanent closure device; (2) preventing tissue erosion; (3) understanding the links between patent foramen ovale, atrial fibrillation, and stroke.

Possible solutions and future directions

There will be both small, incremental improvements as well as large paradigm shifts that occur. A list of important future possibilities is shown in Table 2A and Table 2B.

6.3. Multimodality Fusion Imaging for Structural Interventions

Problem Presenter: Adam Greenbaum, MD

Statement of the problem or issue

Imaging during structural interventions involves 3 levels or categories:

First-level imaging (Figure 1):

• Fluoroscopy or x-ray based.

• Differentiation based on x-ray attenuation by metals, bone/calcium, iodine (but not tissues).

• Identifies devices and accurate placement within a few millimeters.

• Advantages: large field of view; optimal device visualization.

• Disadvantages: 2D only; radiation exposure; cannot image soft tissues.

Second-level imaging (Figure 2):

• Ultrasound (echocardiography)-based.

• Differentiation based on tissue densities.

• Identifies specific tissues and spatial/temporal relationships.

        – Valve leaflets; myocardial chambers, and borders.

• TEE has been the workhorse:

        – 2D; live x-plane; Doppler; 3D; etc.

• ICE is another useful adjunct:

        – Newer catheters with larger field-of-view; live x-plane; 3D; etc.

• Advantages: no radiation; 3D; visualize soft tissues.

• Disadvantages: smaller field-of-view; less depth of view;  shadowing effects.

Third-level imaging (Figure 3):

• New and novel.

• Ultrasound-angiography-CT based.

      – Precise 3D location within tissue.

       – Leaflet-splitting (LAMPOON/BASILICA); removal (CATHEDRAL); suturing (PASTA).

      – Myocardial traversal (mitral cerclage).

      – Myocardial laceration-percutaneous myotomy (SESAME).

• Accuracy within millimeters.

Gaps in knowledge

Fusion imaging is also known as coregistration (Figure 4). These systems attempt to blend several imaging techniques into the same image on a viewing screen.

• Current approaches are in their infancy.

    –  X-ray and echo: EchoNavigator; Truefusion.

    –  X-ray and CT/MR: Heart Navigator; DynaCT.

    –  X-ray and electromagnetic positioning: EAM; CARTO.

• Multiple “live” images vs “live” blended with previously stored images.

• Developing and using reliable fiducial markers.

    –  Bony structures—issues with positioning.

    –  Contrast angio—issues with phase.

• X-rays are “projections” of a 3D structure onto a 2D screen.

3D-CT and 3D-echo: final image is a 2D derivative of a 3D composite.

Motion compensation (cardiac, respiratory) may not be the same for each method.

Can/will fusion imaging reduce radiation doses, contrast use, and procedure times?

Possible solutions and future directions

Developmental work in fusion imaging is underway at a rapid pace. Stereotopic and 3D image displays are being investigated. Partly, it is a question of what do interventionalists want, what do they need, and how can the new imaging techniques make procedures safer and more efficient, or even make the procedures possible at all.

References

1. Khan JM, Bruce CG, Greenbaum AB, et al. Transcatheter myotomy to relieve left ventricular outflow tract obstruction: the septal scoring along the midline endocardium procedure in animals. Circ Cardiovasc Interv. 2022;15(6):e011686. Epub 2022 Apr 5. doi:10.1161/CIRCINTERVENTIONS.121.011686

2. Lederman RJ, Babaliaros VC, Rogers T, et al. Preventing coronary obstruction during transcatheter aortic valve replacement: from computed tomography to BASILICA. JACC Cardiovasc Interv. 2019;12(13):1197-1216. doi:10.1016/j.jcin.2019.04.052

IAGS 2022 Session 7: Hemodynamics Session 1

7.1 Current Role of Hemodynamic Support in Complex, High-Risk PCI

Problem Presenter: Tarek Helmy, MD

Statement of the problem or issue

In recent years there has been a steady increase in the complexity of patients undergoing PCI, both in terms of their coronary anatomy as well as their comorbidities and overall risk profiles. Use of mechanical circulatory support (MCS) for high-risk PCI remains an important but controversial topic. The challenges are multiple, including the basic concepts of when might MCS be needed, that is, what complex coronary anatomy poses greatest risk of hemodynamic compromise, what are the potential benefits of MCS, what type of circulatory support should be used, and which patient populations should be considered for it. At the present time, the 2 major MCS support systems in common use are the intra-aortic balloon pump (IABP) and the Impella device.

Gaps in knowledge

Data for use of MCS in high-risk PCI are limited, but clinical trials are ongoing and these will help better understand and define patients who may derive benefit from hemodynamic support. The BCIS-1 trial¹ compared elective IABP with no IABP in 301 patients (mean LVEF 23% and Jeopardy score ≥8-12). There was no difference in major adverse events (MACCE) at hospital discharge between the 2 groups (15.2% vs 16%; P=.85). Mortality at 6 months was numerically lower in the IABP group but did not reach significance (4.6 vs 7.4%; P=.32) However, viability of jeopardized myocardium distal to target lesions was not assessed. The PROTECT II trial² randomized 448 pts to IABP or Impella 2.5 during elective high-risk PCI. Inclusion criteria were complex multivessel, unprotected left main or last remaining artery, and LVEF ≤30%-35% (mean LVEF of enrolled patients  24%). There were no differences in major adverse events (MAEs) at 30 and 90 days between the 2 groups in the intention-to-treat analysis. Interestingly, the per-protocol analysis showed significant reduction in MAE at 90 days in favor of Impella (40% vs 51%; P=.023). A significant “learning curve” was observed for use of Impella 2.5 for MCS. Additionally, rotational atherectomy (RA) was performed more often in the Impella arm (14.2% vs 9%; P=.083), possibly due to enhanced hemodynamic support, but this led to more post-PCI cardiac biomarker rise. In patients without RA use, MCS with Impella was associated with fewer MAEs at 90 days (35.5% vs 50.5%; P=.003). Unfortunately, this trial was terminated early at an interim analysis so conclusions must be tempered. PROTECT III and RESTORE EF were prospective, multicenter, single-arm post-market-approval studies of Impella in high-risk, nonemergency PCI. Final results of both were presented at the TCT conference in November 2021. In PROTECT III, authors focused on those patients who would have qualified for the PROTECT II randomized trial (PII-like), and compared them with the PROTECT II patients. The PII-like patients in PROTECT III were more “complex” than those in PROTECT II, RA was employed more often, complete revascularization was achieved more often, and there was less bleeding requiring transfusion. MACCE at 90 days was 15.2% in PROTECT III vs 21.9% in PROTECT II (P=.037). In RESTORE EF, the primary outcome comparator was LVEF at 90 days, which improved significantly: mean 35% at baseline to mean 45% at 90 days; P<.001). It is suggested that more complete revascularization in the Impella-supported patients led to this improvement. Additional details on PROTECT III and RESTORE EF await their full publication. While data at present are encouraging for MCS use in high-risk PCI patients in general, and for Impella rather than IABP in particular, many barriers remain. Cost and availability are 2—for example, IABP is less expensive, more widely available, and requires less training and support to operate the device; on the other hand, Impella is more expensive, less widely available, and requires more training and support to operate the device. Another barrier-gap is patient selection: how and with what tools can we assess “high risk?” Importantly, just recently, researchers in the United Kingdom analyzed the BCIS interventional database from 2006-2016, and developed a proposed “CHIP score” for assessing patient risk.³ The score ranges from 0 to 13. Cumulative MACCE was 0.6% with CHIP score of 0, rising to 4.4% with CHIP score ≥5, and much higher beyond that. More widespread investigation of the utility of this score is awaited.

Possible solutions and future directions

The PROTECT IV trial (NCT04763200) is currently enrolling patients into a prospective, multicenter, randomized, parallel-controlled, open-label, 2-arm study. Eligible high-risk patients are randomly assigned to Impella-supported PCI or to standard PCI with or without IABP support. Estimated completion date for enrollment is 2024, with follow-up completed in 2026. Results should help further refine the concept of high risk, whether MCS can be beneficial in high-risk PCI, and which of the 2 devices being compared in the 2 arms might be superior.

References

1. Perera D, Stables R, Thomas M, et al. Elective intra-aortic balloon counterpulsation during high-risk percutaneous coronary intervention: a randomized controlled trial. JAMA. 2010;304(8):867-874. doi:10.1001/jama.2010.1190

2. O’Neill WW, Kleiman NS, Moses J, et al. A prospective, randomized clinical trial of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk percutaneous coronary intervention: the PROTECT II study. Circulation. 2012;126(14):1717-1727. doi:10.1161/CIRCULATIONAHA.112.098194

3. Protty M, Sharp ASP, Gallagher S, et al. Defining percutaneous coronary intervention complexity and risk: an analysis of the United Kingdom BCIS Database 2006-2016. JACC Cardiovasc Interv. 2022;15(1):39-49. doi:10.1016/j.jcin.2021.09.039

7.2. Hemodynamic Support for STEMI: Door to Unloading Times and Do We Need Systems of Care?

Problem Presenter: George Vetrovec, MD

Statement of the problem or issue

Data from randomized trials of primary PCI for STEMI clearly show that both acute and long-term survival are related to infarct size.¹ Importantly, as modern reperfusion therapies like primary PCI (pPCI) have improved survival of the acute infarct event over time, and in-hospital mortality has declined as a consequence, the incidence of later heart failure has increased. ²

Gaps in knowledge

The question arises whether there are measures we can take that will reduce infarct size and reduce the later development of heart failure. Research studies in animal models showed benefits of left ventricular (LV) unloading prior to reperfusion. Based on these, a small clinical pilot trial was performed to determine if LV unloading with Impella for 30 minutes prior to reperfusion in anterior STEMI was possible and safe.  Results showed there was no increase in infarct size with 30 minutes delay to reperfusion.³ Exploratory subgroup analyses showed that larger infarcts had greater protection with LV unloading.  Nevertheless, many other knowledge gaps remain: What is the impact of ischemia time before treatment? What is the optimal unloading time (both pre- and post reperfusion)? What role do medications to reduce blood pressure and heart rate play in optimizing Impella function? What is the required reduction in outcome events needed to decide if unloading is favorable or not?

Possible solutions and future directions

The STEMI-DTU trial (NCT03947619) is currently enrolling patients. This is a prospective, multicenter, randomized, controlled open-label, 2-arm trial.  Patients in the investigative arm will receive an Impella pump, undergo 30 minutes of support prior to reperfusion with pPCI, and then 4-6 hours of support after reperfusion. In the control arm patients will receive usual pPCI immediately. The primary comparator is infarct size measured by cardiac MRI. This trial should generate further insights into the effects of LV unloading on infarct size in STEMI.

References

1. Stone GW, Selker HP, Thiele H, et al. Relationship between infarct size and outcomes following primary PCI: patient-level analysis from 10 randomized trials. J Am Coll Cardiol. 2016;67(14):1674-83. doi:10.1016/j.jacc.2016.01.069

2. Ezekowitz JA, Kaul P, Bakal JA, Armstrong PW, Welsh RC, McAlister FA. Declining in-hospital mortality and increasing heart failure incidence in elderly patients with first myocardial infarction. J Am Coll Cardiol. 2009;53(1):13-20. doi:10.1016/j.jacc.2008.08.067

3. Kapur NK, Alkhouli MA, DeMartini TJ, et al. Unloading the left ventricle before reperfusion in patients with anterior ST-segment-elevation myocardial infarction. Circulation. 2019;139(3):337-346. doi:10.1161/CIRCULATIONAHA.118.038269

7.3 Contemporary Management of Intermediate and High-Risk Pulmonary Embolism

Problem Presenter: Herbert Aronow, MD

Statement of the problem or issue

Hospitalizations for acute pulmonary embolism (PE) are growing and PE now represents the third-leading cause of cardiovascular mortality in the United States. High-risk (also known as “massive”) PE is defined by the presence of prolonged hypotension and/or the need for vasoactive agents, presence of shock, or cardiac arrest. While high-risk PE comprises only ~5% of all PE presentations, its associated mortality is ~30%. Available therapeutic interventions for high-risk PE include systemic full-dose thrombolysis, surgical embolectomy, and catheter-directed mechanical thrombectomy, all with or without extracorporeal membrane oxygenation (ECMO). Randomized controlled trials (RCTs) have found that when compared with anticoagulation, systemic thrombolysis reduces mortality and PE recurrence in high-risk PE patients, but at a cost of major bleeding (including intracranial hemorrhage). Observational studies have yielded mixed results when comparing systemic thrombolysis with catheter-directed therapies (CDTs), and outcomes are similar in studies comparing systemic thrombolysis with surgical embolectomy. However, robust comparative safety and effectiveness data are lacking.

Intermediate-risk (also known as “submassive”) PE is defined as a normal blood pressure without the need for vasoactive agents or other support, but with evidence of right ventricular (RV) dysfunction. Intermediate-risk PE represents 55% of all PE and the in-hospital mortality is variable, ranging from <3% up to 10%. One RCT demonstrated quicker resolution of RV dysfunction, reduction in pulmonary artery systolic blood pressures, and diminution of clot burden with ultrasound-assisted, catheter-directed, low-dose thrombolysis compared with systemic anticoagulation.

Gaps in knowledge

Despite the tremendous evolution in our understanding of PE and its therapies over recent years, many questions remain. Should we manage PE like we manage ST-segment-elevation myocardial infarction and acute ischemic stroke, where speed of therapy is critical and the concept of “time is tissue” applies? For high-risk PE, should CDT with mechanical thrombectomy replace systemic thrombolytics and surgical embolectomy? For intermediate-to-high risk PE, how can we better risk stratify patients to choose among available therapies? Similarly, what is the relative short- and long-term effectiveness of intravenous unfractionated heparin, catheter-directed thrombolysis with or without ultrasound assistance, and mechanical thrombectomy? Also, what are the most appropriate regimens (dose and duration) for catheter-directed thrombolysis? From a device-evolution standpoint, can we improve upon thrombus removal when using catheter-directed mechanical thrombectomy, and do we need to? How might existing therapies impact outcomes beyond survival, recovery of RV function, and pulmonary hemodynamics, such as quality of life (QoL) and functional status? And, finally, what therapies can be most effective for prevention and treatment of chronic thromboembolic pulmonary hypertension (CTEPH)? There is a clear need for additional registry and clinical trial data.

Possible solutions and future directions

Enrollment of patients in available PE registries should permit better characterization of long-term outcomes. Expansion of clinical trial endpoints to include functional status, QoL, cost, and incidence of CTEPH is needed. For high-risk PE patients, RCTs are unlikely to be undertaken, so large observational studies using registries are needed to compare available therapies. For intermediate-high risk PE patients, several ongoing and planned RCTs (eg, HI-PEITHO [ultrasound-facilitated, catheter-directed, thrombolysis vs anticoagulation] NCT04790370, PEERLESS [mechanical thrombectomy vs catheter-directed thrombolysis] NCT05111613, and STRATIFY [low dose systemic thrombolysis vs ultrasound-assisted thrombolysis vs heparin] NCT04088292) will help determine the relative safety and efficacy of available therapies in this ever-growing space. Finally, there is a need for further device innovation allowing for more extensive/distal pulmonary artery thrombectomy and potentially for the combination of mechanical thrombectomy with catheter-directed thrombolysis.

IAGS 2022 Session 8: Endovascular Session 2

8.1 Effectiveness Assessment in PAD: What are the Leading Treatments?

Problem Presenter: George Adams, MD

Statement of the problem or issue

Peripheral artery disease (PAD) affects more than 200 million people worldwide. The primary drivers of the rising prevalence are the ongoing epidemics of diabetes, chronic kidney disease, and an aging population. PAD has a wide spectrum of presentation ranging from asymptomatic disease to typical claudication to limb-threatening ischemia (also called critical limb ischemia, or CLI). Interventions are aimed at improving symptoms of claudication and preventing limb amputation.

Varied clinical presentation is coupled with a similarly wide spectrum of intravascular anatomic disease, which can make treatment challenging from an endovascular perspective. The presence of multilevel disease (iliac, femoral popliteal, infrapopliteal), chronic total occlusions, calcified disease, and long lesions all pose technical challenges and can affect the durability of treatment.

Effective treatment of PAD requires an interventionalist to think outside the box and be familiar with a wide range of techniques and tools to tackle the specific endovascular challenges a patient may pose. The landscape of endovascular devices available for treatment of PAD has grown markedly over the last decade. This offers a great deal of flexibility to the interventionalist. However, it is important to remember the adage that “a carpenter is only as good as his tools.” While new devices are available, it is important that the modern interventionist spend time and effort to become facile in the use of these devices and understand which devices are best suited for which patient.

In particular, CLI is extremely challenging to treat from an endovascular perspective. On the other hand, these patients may also derive the most benefit from successful intervention. Staving off limb amputation can increase the quality of a patient’s life tremendously. However, this requires patience on the part of the interventionalist, and unfortunately, current patterns of reimbursement do not offer economic incentives commensurate with the effort required for successful interventions. As the landscape of peripheral vascular interventions continues to evolve and move away from procedures performed in hospitals to ones performed in outpatient-based labs (OBLs) or ambulatory surgical centers (ASCs), it may change the paradigm and incentive structure. Importantly, multiple studies have demonstrated that procedures performed in the OBL setting have similar safety to those performed in the hospital setting. This may be due in part to the advanced technology available for peripheral vascular interventions.

Gaps in knowledge

Many new devices have been introduced for the treatment of PAD (Table 1). Conventional pathways of approval of these devices need to be re-evaluated. To address unmet needs in PAD, we must explore why certain devices work well in some settings but not others. The case of the drug-coated balloon (DCB) illustrates this point. DCBs were shown to be safe and effective in the treatment of PAD above the knee. However, these devices did not perform as expected below the knee (BTK). This suggests there is substantial heterogeneity in vascular disease at different levels of the arterial tree, and devices must cater to the specific challenges. BTK lesions may be more prone to elastic recoil and have more calcified plaque, which may limit the effectiveness of balloon angioplasty and impair drug delivery. Additional studies investigating these areas are needed for the field to advance.

Possible solutions and future directions

Overall, the field of peripheral vascular interventions has progressed significantly over the last several years, and has evolved rapidly and continuously to meet the challenges of a rapidly growing number of patients who need care. The goal of treatment must be to personalize care and match treatments and setting to the patient’s unique needs. Future research to understand heterogeneity in patients and address the most recalcitrant problems in PAD interventions: restenosis, multilevel disease, and BTK lesions, still awaits us.

8.2 Drug Delivery for Below-the-Knee Interventions: Which Drug and What Platform?

Problem Presenter: James P. Zidar, MD

Statement of the problem or issue

Patients with peripheral arterial disease often present late in the disease course, often with critical limb ischemia. These patients generally exhibit anatomically advanced disease, with long, calcified lesions and chronic total occlusions (CTOs). Vessels typically are small—2.0-3.5 mm—and diabetics especially can have microvascular distal pruning disease. Vessel access can be very problematic, which has led to retrograde pedal artery access techniques just to reach and cross the target lesions. Distal emboli arising from lesions and/or flaked material coatings can be catastrophic and lead to amputation. Restenosis is common with conventional balloon angioplasty (POBA) and stenting, and this has evolved into a “no metal left behind” approach. Drug-coated balloons (DCBs) have so far not proven beneficial: In.Pact Deep, BioLux P-II, and Lutonix BTK clinical trials all had negative primary outcomes. Atherectomy with directional or orbital devices have not directly improved outcomes, but may be useful techniques for lesion preparation. Interestingly, laser angioplasty, and even more recently Shockwave lithoplasty, have both shown some promise in preparing the target lesion.

Gaps in our current knowledge

While drug delivery to target lesions below the knee seems to offer promise, there are many challenges to this approach. With drug-coated materials, there is increased risk of emboli from flaking off of large coating particles; this can lead to drug loss in transit to the target site, which in some models exceeds 50%. The goal is to deliver the full drug dose to the target lesion while navigating through the vasculature, protecting the drug from loss during transit while avoiding particulate emboli and potential downstream ischemia. Beyond this, the goals are to ensure timely, consistent, and accurate drug delivery/transfer from balloon to target lesion with full, intended, and consistent dosing.

Other knowledge-gap questions:

• Can the full drug dose be deployed to the target lesion during angioplasty?

• Can we ensure mural uptake of therapeutic drug doses?

• How can we prevent rapid drug degradation and/or diffusion away from target site?

• How can we sustain drug release over the critical time period required?

• Can we mimic the drug-release pharmacokinetics of efficacious permanent implants (DES)?

• Are there better ways to deliver antiproliferative agents to the vessel wall for more durable results?

• Would a bioabsorbable vascular scaffold (ABSORB) offer benefits?

• How can we access the intracellular space with sufficient drug levels to exert desired therapeutic effects?

Possible solutions and future directions

This will be a potent area of research over the next 3 years. Below are 3 examples of novel technologies moving through the clinical pathway towards device approval.

(1) Virtue SAB: sirolimus-weeping balloon (Orchestra BioMed)

• Proprietary weeping balloon technology that protects drug during transit to prevent potential for downstream ischemia from particulate debris.

• Performs angioplasty using standard catheter techniques.

• Consistently delivers intended dose and enables focal drug uptake.

• Provides extended focal release through the critical healing period.

(2) Selution SLK: sirolimus-eluting balloon with sustained release (MedAlliance)

• Proprietary microreservoirs with cell-adherent technology.

• Creates microreservoirs combining sirolimus and biodegradable polymer via a proprietary amphipathic lipid technology with binds microreservoirs to the balloon surface.

• Contains and protects microreservoirs during insertion and inflation.

• Enhances drug retention and bioavailability, allowing for a lower drug dose concentration on the balloon surface (1 μg/mm).

(3) ESPRIT BVS: bioabsorbable vascular scaffold (Abbott)

• Updated thinner BVS from the coronary Absorb BVS.

• PLLA slowly degradable polymer loaded with everolimus.

• 99 micron strut thickness with sizes from 2.5-4.0 mm.

• Scaffold lengths up to 38 mm.

• Delivers everolimus to the vessel wall over many months.

• Polymer slowly degrades over 2 years.

8.3 Deep Venous Arterialization for Critical Limb Ischemia

Problem Presenter: Jihad A. Mustapha, MD

Statement of the problem or issue

Deep venous arterialization (DVA) is a hot topic currently, but it isn’t new. The process was first documented in 1912 by Dr A.E. Halstead, advanced by Dr F. Lengua in Peru, and then recently brought into the endovascular arena by several pioneers in vascular surgery. Initially with this form of treatment, patient selection was considered very conservative, including only Rutherford class 6 limb salvage cases. Based on results from the early pioneers, multiple physicians began arterial-to-venous flow reversal using off the shelf technology. The techniques evolved rapidly over a relatively short period of time. Early on it was learned that the venous valves needed to be addressed and these were treated with balloon angioplasty alone. Valve treatment advanced with the use of cutting balloon angioplasty. Evolution continued with the plantar vein accessed in a retrograde fashion combined with antegrade common femoral artery access. There were other technical variations, all of which led to positive outcomes in terms of limb salvage for patients deemed nonsalvageable. It was learned that higher arterial pressures were necessary to deliver high perfusion pressure into the veins in the foot, otherwise stagnant flow in the foot could lead to higher rates of acute or delayed thrombosis. Today, it is recommended that the inflow for the DVA reversal should be at an arterial conduit level that is viable, contractile, and able to deliver high pressure flow rates. Multidisciplinary collaboration is required to ensure positive patient outcomes, with attention to postprocedure swelling, pain, forefoot surgical debridement, and minor amputation stump management. Wound care specialists and podiatrists must be well-acquainted with the pathophysiology and anatomy in the specific patient setting of swelling and pain. The importance of not transecting the reversed plantar veins is critical. Results from the PROMISE I trial showed high procedural success and improved limb salvage for patients otherwise deemed “no-option” cases.¹ Moving forward, the PROMISE II trial (NCT03970538) has just concluded enrollment.

Gaps in knowledge

We don’t understand completely the exact mechanisms of neovascularization that appear when both antegrade venous flow as well as remnant arterial collateral flow exist. DVA conduit maturation and subsequent tissue perfusion appear to require about 4-6 weeks for tissue granulation to start. Immediately after DVA, symmetric arterial-to-venous flow throughout the foot is seen. But by 6-12 weeks after DVA, both brisk flow and delayed filling of arterialized veins in the digits are noted. We don’t understand the mechanisms for this presently.

We also see delayed arterialization of flow migrating toward the wound area and are unsure whether progenitor cells or signals from the wound are directing angiogenesis toward the area with the highest need for oxygenation. The most curious component of DVA is the fact that, after the procedure is performed and patients’ wounds are healed and doing well, a DVA that then occludes doesn’t seem to make any difference regarding recurrence of ulcers. Interestingly, patients tend to continue to remain asymptomatic and do well clinically. It is not understood why angiography at 6 months and beyond shows the antegrade neovascularization to remain at the highest level despite the DVA conduit being occluded.

The arterialized veins tend to have severely hyperplastic tissue generation right at the junction of the stent grafts and less of it distal from the grafts. It is not understood why the hyperplasia happens in this area. This is one of the Achilles’ heels for DVA.

Possible solutions and future directions

Patient selection for DVA should be expanded beyond “no-option patients.” For example, a patient with a wound in the distribution of one of the tibial arteries and who has failed revascularization by any means should be considered for DVA to ensure oxygenated blood is delivered to the non-healing wound. DVA should be considered for Rutherford class 4 patients. While patients who are Rutherford class 4 may be viewed as “functional patients” to many health care providers, the patients very often do not view themselves the same way. Often these patients can be even less functional than Rutherford class 5 patients who don’t have sensation and therefore have no pain in their feet.

Multidisciplinary DVA teams should be standardized to provide the most efficient long-term benefit to patients who receive the complex DVA procedure. The team should include wound care specialists, podiatry, vascular surgery, endovascular specialists, vascular medicine, and infectious disease. Very importantly, the primary care physician (PCP) must remain involved to address comorbidities, especially chronic kidney disease (CKD) and diabetes, which are prevalent in these patients. It is important to monitor changes in foot tissue color (mottling, cyanosis) after the procedure. Establishing protocols to preserve native arterial perfusion and management of pedal loop outflow is critical during the DVA maturation process.

Reference

1. Clair DG, Mustapha JA, Shishehbor MH, et al. PROMISE I: early feasibility study of the LimFlow System for percutaneous deep vein arterialization in no-option chronic limb-threatening ischemia: 12-month results. J Vasc Surg. 2021;74(5):1626-1635. doi:10.1016/j.jvs.2021.04.057

IAGS 2022 Session 9: Emerging Therapies Session 1

9.1 Coronary Sinus Reduction for Refractory Ischemia

Problem Presenter: Amir Lerman, MD

Statement of problem or issue

Chronic angina, refractory to medical or interventional therapies, is a common and disabling medical problem affecting more than 100 million people worldwide.¹ It is the most common symptom of myocardial ischemia. Patients with chronic angina may have obstructive or nonobstructive coronary disease that is unsuitable for revascularization. Furthermore, a substantial number of patients (more than 30%) continue to suffer from angina following a “successful” revascularization. In patients with angina and no significant obstructive coronary disease, more than 40% have microvascular disease present.

Coronary sinus reduction to treat angina was pioneered by a cardiac surgeon, Dr Claude Beck.² Between 1948 and 1964, Beck treated more than 1000 patients surgically with a partial ligation of the coronary sinus, achieving very good results. The physiological basis for this is illustrated in Figure 1.³ Obstructive coronary artery disease, either epicardial or microvascular, alters the epicardial-to-endocardial flow ratio (Epi/Endo) such that ischemia can exist. Partial obstruction of the coronary sinus raises venous pressure in the intramyocardial veins, restoring the Epi/Endo ratio back to a more normal value.

Gaps in knowledge

While the surgical approach to coronary sinus reduction is no longer undertaken, a number of percutaneous devices have been developed to achieve this goal. The intermittent occlusion procedure PICSO (pressure-controlled intermittent coronary sinus occlusion) was tested and found to be helpful in reducing infarct size and ischemia both in animal models and in STEMI patients.^4-6 More recently, a novel stent device placed into the coronary sinus via a balloon catheter has been successfully used. The efficacy of this approach was tested in preliminary studies, and a larger-scale evaluation is currently underway. It is important to point out that we do not know for certain what patient groups might benefit.

Possible solutions and future directions

The transcatheter coronary sinus reducer has been tested in small clinical studies and a small randomized trial of 104 patients.⁷ A much larger randomized trial, COSIRA II (NCT05102019), involving several hundred patients, is now underway. Enrollment is expected to be completed in 2024, with results available in 2028. Moreover, the effectiveness of the coronary sinus reducer in improving coronary microvascular function and angina is being investigated in an early phase study (NCT045231682).

References

1. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1459-1544. Erratum 2017;389(10064):e1 doi:10.1016/S0140-6736(16)31012-1

2. Beck CS, Leighninger DS. Scientific basis for the surgical treatment of coronary artery disease. J Am Med Assoc. 1955;159(13):1264-1271. doi:10.1001/jama.1955.02960300008003

3. Ielasi A, Todaro MC, Grigis G, Tespili M. Coronary sinus reducer system: A new therapeutic option in refractory angina patients unsuitable for revascularization. Int J Cardiol. 2016;209:122-130. Epub 2016 Feb 3. doi:10.1016/j.ijcard.2016.02.018

4. Mohl W, Gangl C, Jusić A, Aschacher T, De Jonge M, Rattay F. PICSO: from myocardial salvage to tissue regeneration. Cardiovasc Revasc Med. 2015;16(1):36-46. doi:10.1016/j.carrev.2014.12.004

5. van de Hoef TP, Nijveldt R, van der Ent M, et al. Pressure-controlled intermittent coronary sinus occlusion (PICSO) in acute ST-segment elevation myocardial infarction: results of the Prepare RAMSES safety and feasibility study. EuroIntervention. 2015;11(1):37-44. doi:10.4244/EIJY15M03_10

6. De Maria GL, Alkhalil M, Borlotti A, et al. Index of microcirculatory resistance-guided therapy with pressure-controlled intermittent coronary sinus occlusion improves coronary microvascular function and reduces infarct size in patients with ST-elevation myocardial infarction: the Oxford Acute Myocardial Infarctio—Pressure-controlled Intermittent Coronary Sinus Occlusion study (OxAMI-PICSO study). EuroIntervention. 2018;14(3):e352-e359. doi:10.4244/EIJ-D-18-00378

7. Verheye S, Jolicœur EM, Behan MW, et al. Efficacy of a device to narrow the coronary sinus in refractory angina. N Engl J Med. 2015;372(6):519-527. doi:10.1056/NEJMoa1402556

9.2: Current Status of Renal Denervation to Treat Hypertension

Problem Presenter: Tim A. Fischell, MD

Statement of the problem or issue

Hypertension remains the leading cause of cardiovascular morbidity and mortality throughout the world. Approximately 30% of adults worldwide and up to 50% of adults in the United States (US) currently suffer from hypertension. Current US national guidelines for target systolic blood pressure are now set at 130 mm Hg. This value is based on compelling data from the SPRINT trial.¹ Furthermore, it turns out that as little as 10 mm Hg reduction in systolic blood pressure yields substantial reduction in risks of stroke, heart attack, and death. One of the biggest challenges is that only 30%–40% of all individuals with hypertension are currently achieving guideline-based blood pressure reduction. Some of this is due to failure to recognize the presence of hypertension, in other cases it is inadequate prescription of medications, and in many other cases it is related to medication noncompliance, which remains a profound problem. Given all these challenges in medication treatment for hypertension, there is a potential role for device-based blood pressure management (renal denervation; RDN). Safe and effective device-based therapies could provide potentially useful alternative treatments that may lower blood pressure successfully.

Gaps in our knowledge

Renal denervation attempts to disrupt sympathetic nerve flow from the kidney to the medulla of the brain stem (afferent signal) and also inhibits efferent nerve fibers from brain stem to kidney. The efferent nerves are important in the release of renin as well as aldosterone. Recent data from a pivotal, randomized, sham-controlled study has shown meaningful BP reduction that is observable over the entire 24 hours of a day (the “always on” phenomenon).² The gaps in our knowledge in RDN relate to questions of efficacy. There are now small, randomized, sham-control trials and a large meta-analysis showing efficacy of RDN,³ but the results from the largest pivotal trial (On-Medication) are still pending. Other questions remain as to the best technique for RDN, which include radiofrequency (RF) thermal ablation, thermal ablation with ultrasound, and chemical ablation. The longer-term efficacy and safety of these various techniques have not yet been fully defined, although data are accumulating. One of the more intriguing gaps in our knowledge is the issue of “nonresponders,” and whether we can determine by upfront testing who will get the best blood pressure lowering response following RDN. Finally, there are still questions about the optimal population who may benefit from this therapy, if and when it is FDA approved.

Possible solutions

We await the results of the ongoing large pivotal trial from Medtronic (SPYRAL HTN-ON MED, NCT02439775). These data will be extremely helpful in establishing the safety and efficacy of RF RDN. Other studies that are currently underway include large randomized trials using thermal ablation with ultrasound (RADIANCE-HTN, SOLO and TRIO Cohorts, ReCor Medical, NCT02649426), and chemical RDN with alcohol using the Peregrine system from Ablative Solutions (TARGET BP 1, NCT02910414). Additional technologies developed in the future to assist with RDN may include direct nerve sensing and/or stimulation, which might help predict patients who will get better responses, as well as quantifying the precise degree of denervation achieved by the procedure. Finally, there are some intriguing early data regarding genetic testing, which may eventually enable providers to select RDN for individuals identified to be the “best responders” to RDN.  If the currently ongoing randomized trials demonstrate good safety and efficacy, it is believed that RDN can become an important tool in the management of patients with poorly controlled hypertension.

References

1. The SPRINT research group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373(22):2103-2116. doi:10.1056/NEJMoa1511939

2. Bohm M, Kario K, Kandzari D, et al. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicenter, randomized, sham-controlled trial. Lancet, 2020; 395(10234):1444-1451. doi:10.1016/S0140-6736(20)30554-7

3. Ahmad Y, Francis DP, Bhatt DL, Howard JP. Renal denervation for hypertension. A systematic review and meta-analysis of randomized, blinded, placebo-controlled trials. JACC Cardiovasc Interv. 2021;14:2614-2624. doi:10.1016/j.jcin.2021.09.020

9.3 Ultra–High-Definition (UHD) Imaging in the Catheterization Laboratory

Problem Presenter: Salman A. Arain, MD

Statement of the problem or issue

Digital angiography is the gold standard for imaging vascular structures in the cardiac catheterization laboratory. However, it has several features which limit its utility during complex coronary and microvascular interventions (Table 1). Image resolution with digital angiography is a critical factor in success of percutaneous vascular interventions, particularly those involving small-sized (<4 mm diameter) blood vessels and/or complex maneuvers. Current flat panel detectors (FPD) have a resolution of 154-200 µm. However, a new ultra–high-definition (UHD) imaging system can acquire images at a resolution of 76 µm.

Gaps in knowledge

Practical utility of UHD imaging has not been extensively demonstrated. To overcome this gap, we studied the utility of a new UHD imaging system during percutaneous cardiac and vascular procedures in our catheterization lab. We report 4 representative scenarios in which UHD imaging was able to overcome the limitations of standard FPD. In each case, the hi-def mode was activated at the operator’s discretion, and standard FPD images were used for qualitative comparison.

In the first case, UHD enabled us to diagnose stent fractures and avulsion in a patient with prior tibial stents that were not apparent by standard FPD imaging even at high magnification. The improved visibility with UHD allowed us to manipulate wires easily and then accurately position a new stent at the bifurcation of the tibioperoneal trunk. In our second example, UHD enabled us to deploy stents with a high degree of precision during a complex left main artery intervention. Extreme angulation and calcification at the origin of the branch vessels made it difficult to use intravascular ultrasound in this situation. Our third case highlighted the utility of UHD imaging in troubleshooting and successfully completing the removal of a partially deformed inferior vena cava filter after conventional imaging techniques failed. Our fourth case demonstrated the use of UHD in performing angioplasty of the digital arteries of the hand (diameter <1.5 mm) in a patient with critical ischemia secondary to refractory Raynaud’s phenomenon. Importantly, all 4 cases were successfully completed without significantly increasing radiation exposure to the patients.

Possible solutions and future directions

The success of complex coronary and peripheral vascular interventions depends upon the operators’ ability to accurately visualize vascular anatomy and precisely maneuver and deploy devices. Most commercially available FPD systems render images with a resolution of 154-200 µm. A new UHD system can render images with much higher resolution of 76 µm.  The safety and applicability of this technology has already been established for neurointerventional procedures.¹ We found that UHD imaging can likewise be useful in coronary and peripheral interventional procedures without increasing either procedure time or radiation exposure. UHD imaging allowed operators to resolve ambiguities in vascular anatomy, facilitate delivery of interventional equipment, and detect structural anomalies in malfunctioning devices. Furthermore, the availability of UHD enabled us to devise new procedures such as digital angioplasty to treat refractory hand ischemia in a patient with Raynaud’s phenomenon (Figure 1). Additional studies are needed to better define the role and optimal integration of UHD imaging into contemporary interventional practice.

Reference

1. Setlur Nagesh SV, Vakharia K, Waqas M, et al. High-definition zoom mode: a high resolution x-ray microscope for neurointerventional treatment procedures. J Neuroimaging. 2019;29(5):565-572. doi:10.1111/jon.12652

IAGS 2022 Session 10: Coronary Session 3

10.1 Latest Techniques and Devices for CTO Intervention: Will They Expand Indications?

Problem Presenter: Khaldoon Alaswad, MD

Statement of the problem or issue

In the latest ACC/AHA/SCAI guidelines, percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) was downgraded from a Class IIa to Class IIb recommendation, based on poorly executed clinical trials.¹ On the other hand, it is admittedly difficult to conduct large randomized clinical trials (RCTs) for CTO-PCI to inform our guidelines appropriately.

Gaps in our knowledge

Most large RCTs comparing PCI vs medical therapy either excluded patients with CTO, or the CTO was frequently left unrevascularized. The largest 2 randomized clinical trials of CTO-PCI vs medical therapy, DECISION-CTO and EUROCTO, both suffered from slow enrollment and failed to enroll the prespecified number of patients.^2,3 Furthermore, in addition, there is a lack of information about the impact of successful CTO-PCI on the long-term outcomes of patients in several specific settings of interest: post STEMI, patients with acute coronary syndromes (NSTEMI/unstable angina), patients with left main (LMCA) disease, and patients with low left ventricular ejection fraction (LVEF). The role of CTO-PCI in achieving complete revascularization has not been investigated in an RCT.

The decision to downgrade the recommendation for CTO-PCI in the latest ACC/AHA/SCAI guidelines was heavily based on the DECISION-CTO trial.² The primary endpoint of DECISION-CTO was a composite of death, myocardial infarction, stroke, or any revascularization. Health-related quality of life (QoL) was assessed at baseline and at 1, 6, 12, 24, and 36 months. The intention-to-treat analysis of DECISION-CTO showed no reduction in the primary endpoint at 4 years in the group that received CTO-PCI vs the group that received medical therapy (22.3% vs 22.4%; HR, 1.03; 95% CI, 0.77-1.37; P=.86). Both the CTO-PCI and no-CTO-PCI strategies were associated with significant improvements in health-related QoL indices, but without between-group differences sustained through 36 months. The DECISION-CTO trial suffered from multiple design flaws. First, because the study did not enroll the targeted number of patients the statistical power was reduced to only 64%. Secondly, 20% of patients assigned to the medical therapy arm crossed over to the CTO-PCI arm within 3 days of randomization. The slow enrollment in the trial indicates that investigators did not enroll highly symptomatic patients; in fact, 13%-14% of the enrolled patients were asymptomatic and had “silent ischemia.” Most importantly, the DECISION-CTO trial did not isolate the effect of a CTO on the patients’ QoL because two-thirds of the patients who were randomized to medical therapy received PCI of non-CTO coronary lesions. In reality, DECISION-CTO compared revascularization of all non-CTO lesions plus medical therapy (an incomplete revascularization strategy) to complete revascularization plus medical therapy (ie, a complete revascularization strategy). The results of DECISION-CTO do not reliably add to our knowledge about CTO-PCI effects on hard endpoints and health-related QoL measures.

The EUROCTO trial showed different outcomes than DECISION-CTO, because it randomized patients to CTO-PCI vs optimal medical therapy (OMT) alone, only if they continued to have angina after both OMT and revascularization of all non-CTO lesions was achieved.³ The primary endpoint was the change in health status QoL assessed by the Seattle angina questionnaire (SAQ) between baseline and 12-month follow-up. This trial showed significant improvement in the QoL (SAQ) in the CTO-PCI arm compared with the OMT arm. However, clinical adverse events (major cardiovascular and cerebrovascular adverse events; MACCE) were no different between the 2 groups at 12 months (6.7% vs 5.2%; P=0.55). This trial also suffered from slow enrollment and had to be stopped early; however, this trial retained better statistical power than the DECISION-CTO trial.

Possible solutions and future directions

CTO-PCI continues to be technically challenging, perceived as high risk, and understudied in RCTs comparing revascularization vs medical therapy. CTO-PCI has been shown to improve QoL in real-world registries, while only 3 relatively small randomized trials demonstrated a QoL improvement after CTO-PCI.^3–5 The difference between registries of CTO-PCI and clinical trials might be explained by an inherent bias to only enroll less symptomatic and lower-risk patients in the clinical trials, which will bias the outcomes of the trials toward the null hypothesis. In addition to this bias against randomizing severely symptomatic patients, several other barriers prevent conducting a large RCT to investigate efficacy and safety of CTO-PCI. First, CTO-PCI is technically challenging, with high failure rates outside of expert centers, which if these non-expert centers participate will bias the results toward the null hypothesis in any intention-to-treat analysis. Secondly, because of generally low adverse clinical event rates, a large number of patients need to be enrolled to achieve sufficient statistical power. This can be challenging too. Finally, only a few expert PCI operators can achieve high success and safety rates with CTOs. As a result of all these factors, a meaningful CTO-PCI trial will be costly and very slow to enroll the required number of patients. Despite these difficulties, a sham-controlled CTO-PCI trial will be necessary to demonstrate the real effect of CTO-PCI on QoL in patients who are highly symptomatic at baseline.

References

1. Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI Guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(2):e21-e129. Epub 2021 Dec 9. doi:10.1016/j.jacc.2021.09.006

2. Lee SW, Lee PH, Ahn JM, et al. Randomized trial evaluating percutaneous coronary Intervention for the treatment of chronic total occlusion. Circulation. 2019;139:1674-1683. doi:10.1161/CIRCULATIONAHA.118.031313

3. Werner GS, Martin-Yuste V, Hildick-Smith D, et al. A randomized multicentre trial to compare revascularization with optimal medical therapy for the treatment of chronic total coronary occlusions. Eur Heart J. 2018;39(26):2484-2493. doi:10.1093/eurheartj/ehy220

4. Obedinskiy AA, Kretov EI, Boukhris M, et al. The IMPACTOR-CTO trial. JACC Cardiovasc Interv. 2018;11(13):1309-1311. doi:10.1016/j.jcin.2018.04.017

5. Badoian AG, Krestyaninov OV, Khelimskii DA, Ibragimov RU, Naydenov RA. Predictors to quality of life improvements in patients with chronic coronary total occlusion depending on the selected treatment strategy. Comp Iss Cardiovasc Dis. 2021;10(2):72-83. doi:10.17802/2306-1278-2021-10-2-72-83

10.2 Management of Coronary In-Stent Restenosis: Are DCBs the Answer?

Problem presenter: Cindy L. Grines, MD

Statement of the problem or issue

Drug-eluting stents significantly reduce restenosis compared with bare-metal stents, but when restenosis does occur, it is often more difficult to manage. Placement of additional drug-eluting stents inside the restenotic lesion reduces but does not eliminate the risk of more neointimal hyperplasia (NIH). Furthermore, this stent “sandwich” adds multiple metallic layers inside the vessel, further reducing the lumen and making it more rigid and difficult to dilate. These additional stent layers may jail or even occlude coronary side branches, resulting in angina or myocardial infarction. A more prolonged course of dual-antiplatelet therapy is required, increasing the risk of bleeding. Conversely, a drug-coated balloon (DCB) contains the active antiproliferative medication to reduce NIH and restenosis, but does not require a bulky, permanent stent to deliver this medication to the target coronary wall.

Several studies have shown DCBs can reduce restenosis and the need for subsequent coronary revascularizations, and the European Guidelines have given DCBs the highest (class 1A) recommendation. Importantly, DCBs are approved and in use in most other countries except the United States (US). The AGENT trial (NCT04647253), a multicenter, pivotal trial required for FDA approval in the US, will randomize patients with coronary in-stent restenosis to treatment with DCB compared with standard balloon angioplasty. This trial is scheduled to be completed in 2024.

Gaps in knowledge

Some intravascular imaging studies have shown the in-stent “restenosis” may be due to lack of full stent expansion rather than NIH. Other restenotic lesions may be due to neoatherosclerosis rather than NIH, and these new lesions can be more difficult to treat. Should operators routinely use OCT/IVUS in restenotic lesions to determine adequate stent expansion and the mechanism of the restenosis? Does the pattern of drug-eluting stents restenosis (edge, focal in-stent, diffuse, proliferative, or total occlusion) influence the risk of subsequent restenosis and thus the choice of treatment?

Although DCBs and drug-eluting stents are both considered class 1A for management of restenosis in the European guidelines, the RIBS IV randomized study found that drug-eluting stents were superior to DCBs.¹ However, this may be due, in large part, to suboptimal lesion preparation with DCB. Studies have shown if the DCB-to-stent ratio was at least 0.90, residual stenosis <20%, and >60 seconds DCB inflation time, then target-lesion failure occurred in only 8% of these optimized lesions.² In the ISAR DESIRE-4 study, use of a scoring balloon was superior to balloon angioplasty for lesion preparation prior to DCB.³ However, there is no standard agreement regarding optimal lesion preparation prior to DCB. This lack of consistency in preparation techniques may influence outcomes in the ongoing AGENT trial.

Other gaps

Although most of us would place a second stent to treat in-stent restenosis, when would one worry about the number of layers of stent before switching to DCB?

• Calcified vessels and multiple stent layers make subsequent stent expansion difficult. Which technique or device is best suited to safely expand old stents?

• What is the best drug for DCB? Can newer preparations allow drugs in the limus-family to be retained in the vessel wall and prolong their therapeutic effects?

• Should we worry about paclitaxel DCB given the scare from the peripheral DCB experience?

Possible solutions and future directions

Intravascular imaging may be essential, both during initial stent implantation to assure that the first stent is optimally deployed, but also if the patient returns to determine the mechanism of restenosis. Some argue that OCT is preferred over IVUS, given its ability to determine depth of calcium and neoatherosclerosis. It is also advocated that guidelines be revised to Class 1, Level of Evidence B, to strongly encourage imaging for in-stent restenosis, given that stent under-expansion is a significant cause of “restenosis.”

Calcified vessels or multiple layers of stent make subsequent stent expansion difficult. There is a wide variety of opinion regarding which technique or device is best suited to safely expand old stents. Initial ultra–high-pressure inflations with noncompliant balloons could be followed by laser “bomb,” intravascular lithotripsy, or atherectomy, and then additional high-pressure inflations performed. However, data are limited and multicenter registries and randomized trials would be necessary to determine risk-to-benefit ratio.

Although many interventional cardiologists would place a second stent to treat in-stent restenosis, there are concerns about adding subsequent stent layers. Restenosis tissue seems difficult to compress between stent sandwiches, and some advocate debulking of tissue. In addition, use of DCB seems promising, especially if the lesion could be adequately prepared with cutting or scoring balloons. Ultimately, randomized trials will be necessary to determine the best lesion preparation of restenosis lesions.

What is the best antiproliferative drug for DCB? Can newer preparations allow drugs in the limus family to have better retention in the vessel wall and prolong their therapeutic effects? Drug and device development in this area should be strongly encouraged.

References

1. Alfonso F, Pérez-Vizcayno MJ, Cuesta J, et al. 3-year clinical follow-up of the RIBS IV clinical trial: a prospective randomized study of drug-eluting ­balloons versus everolimus-eluting stents in patients with in-stent restenosis in coronary arteries previously treated with drug-eluting stents. JACC Cardiovasc Interv. 2018;11(10):981-991. doi:10.1016/j.jcin.2018.02.037

2. Lee HS, Kang J, Park KW, et al. Procedural optimization of drug-coated balloons in the treatment of coronary artery disease. Catheter ­Cardiovasc Interv. 2021;98(1):E43-E52. Epub 2021 Jan 25. doi:10.1002/ccd.29492

3. Kufner S, Joner M, Schneider S, et al. Neointimal modification with scoring balloon and efficacy of drug-coated balloon therapy in patients with restenosis in drug-eluting coronary stents: a randomized controlled trial. JACC Cardiovasc Interv. 2017;10(13):1332-1340. doi:10.1016/j.jcin.2017.04.024

10.3 Left Main Disease: How to Assess and When to Intervene in Patients With Aortic Valve Disease

Problem Presenter: Ayman Magd, MD

Statement of the problem or issue

Left main coronary artery disease often presents a diagnostic dilemma, and the concomitant presence of aortic stenosis (AS) can make precise evaluation even more complicated. Intracoronary injection of nitroglycerin during diagnostic angiography often helps resolve the issue in assessing borderline left main lesions. In other patients, AS may create uncertainty that ultimately is due to anatomical and physiological changes in the left ventricle as the result of concentric hypertrophy (LVH). Coronary flow reserve (CFR) may be impaired when the effective orifice area of the left main is <1.0 cm². This is due to adaptive up-regulation of baseline flow to meet the oxygen demands of the hypertrophied ventricle, thereby diminishing any further up-regulation when hyperemia is induced, and giving an impaired CFR, which will often normalize upon relief of the AS. Moreover, endothelial dysfunction in these patients also impairs CFR. IVUS may be helpful though imprecise. Recent data have shown that a minimal lumen area (MLA) of >4.5 mm in the left main indicates a nonsignificant stenosis, however, approximately 25% of those patients will still have an ischemic FFR <0.8. While an MLA <6 mm has been suggested as a threshold to denote ischemia, still 36% will have an FFR >0.8. Recent observational data highlight significant limitations of physiological assessment using CFR in this setting due to a combination of LVH, increased ventricular cavity size, and decreased diastolic perfusion from external compression with subendocardial ischemia. Issues regarding the safety of using a vasodilator in these patients have turned attention to FFR and iFR as possible aids in the assessment of left main lesions in patients with AS. As described above, data have shown they may overestimate lesions and often they will improve after aortic valve replacement. Accordingly, it is currently suggested that more stringent criteria should be used such that an iFR <0.82 would denote ischemia while an iFR >0.93 implies no ischemia.

Gaps in knowledge

Once a significant left main stenosis is detected, decisions regarding the optimal mode of treatment become quite complex. Currently, TAVR has been shown in comparative trials to be at least as effective as surgery (SAVR) for AS alone, with reassuring long-term outcomes data. Consideration of percutaneous solutions to coexisting AS and left main disease entails ensuring an outcome similar to that achievable with surgery. Randomized controlled trials have shown narrowing of the gap between PCI and CABG, with some remaining issues to be considered. The EXCEL trial IVUS substudy analyzed the relationship between final achieved post-PCI minimal stent area (MSA) and clinical outcomes.¹ Three equal-sized groups were analyzed according to final MSA: Group 1 (MSA 4.4-8.7 mm), Group 2 (MSA 8.8-10.9 mm), and Group 3 (MSA 11-17.8 mm). Patients in Group 3 with the largest final MSA had the lowest event rates, with a 3-year stent thrombosis rate of 0% vs 3.1% in Group 1 (the smallest final MSA group). Cardiac mortality at 3 years was also significantly lower in Group 3 compared with Group 1 (1.9% vs 6.9%; P=.02).² The authors suggested that a cutoff value of 9.8 mm final MSA was the desired criterion to ensure optimal long-term outcomes. Although these data highlight the importance of achieving (an eagerly awaited) precise IVUS measurement during the PCI procedure rather than using the vague term “IVUS optimization,” they also warrant a deeper dive to explore why this criterion could not be achieved in a large percentage of these patients despite IVUS use in 77% of cases. Although no explanation was given, possible causes are: variations in size of the left main relative to body size, variations in vessel diameter even among similar-sized individuals, as well as variations in vessel geometry since some patients have a conical-shaped artery, a biconcave artery, or a tapered or funnel-shaped vessel, among others. Of note, recent data have shown that patients in whom post-PCI iFR >0.95 was achieved had the lowest long-term event rates. Hopefully, these intraprocedural criteria will help PCI close the gap vs surgery for these patients. A final question to ponder: patients live longer after CABG due to the superiority of the LIMA-LAD conduit even if vein grafts to the left circumflex and right coronary arteries close, which they often do. Accordingly, will we need to perform complex bifurcation stenting of the left circumflex, which may jeopardize the LM-LAD stent and hinder long-term outcomes?

Possible solutions and future directions

A critical factor in treating left main lesions will be optimal pre-stent lesion preparation using plain balloons, cutting balloons, atherectomy (rotational or orbital), and possibly lithotripsy which could, via deeper fractures of calcium, ensure abolition of resistance to optimal stent expansion, an issue which itself requires further studies. Imaging during these difficult left main PCI procedures will be critical to ensure optimal final outcomes.

References

1. Maehara A, Mintz G, Serruys P, et al. Impact of final minimal stent area by IVUS on 3-year outcome after PCI of left main coronary artery disease: the EXCEL trial. J Am Coll Cardiol 2017;69(11 Suppl):963. doi:10.1016/S0735-1097(17)34352-8

2. Maehara A. IVUS-guided left main and non-left main stenting in the EXCEL trial: lessons from the EXCEL-IVUS core laboratory. TCT 2016.

IAGS 2022 Session 11: Health Care Delivery and Industry Session

11.1 Impact of COVID-19 on Cardiovascular Disease

Problem Presenter: Timothy Henry, MD

Statement of the problem or issue

The care of patients with cardiovascular disease has been dramatically affected by the COVID-19 pandemic with both direct and indirect effects (Figure 1).^1,2

The COVID-19 virus has a variety of deleterious influences on endothelium, the vasculature, and the myocardium, mostly related to proinflammatory and prothrombotic effects. These lead clinically to increases in deep venous thrombosis, pulmonary emboli, stroke, and acute myocardial infarction (AMI), generally occurring within the first month of active disease. Patients with a history of cardiovascular disease and those with cardiovascular risk factors (especially hypertension and diabetes) are at increased risk for complications of COVID-19, including longer hospitalizations and higher mortality. Myocardial injury, based on elevated troponin levels, occurs in 20%-40% of hospitalized COVID-19 patients and is associated with further increased risk of mortality. Interestingly, microthrombi leading to STEMI or NSTEMI has been a novel presentation of COVID-19. Patients with sustained symptoms or “long COVID” appear to have increased risk of microvascular dysfunction.

The indirect effects of the COVID-19 pandemic have been just as dramatic, with disruption in clinical care pathways and other healthcare processes. Public health measures taken to prevent spread of the virus, including cancellation or deferral of elective procedures and in-person appointments, along with restrictive visitation policies and lockdowns, led to barriers in care delivery on the one hand, as well as reluctance of patients to obtain both elective and emergent cardiovascular care on the other hand. For example, there was a 25%-40% reduction in patients presenting with STEMI throughout the world, coupled with significant time delays at every step for those who did present to the hospital. This resulted in a significant increase in mortality in patients with STEMI, as well as higher rates of out-of-hospital cardiac arrest, cardiogenic shock, and late complications (including papillary muscle dysfunction, ventricular septal and free wall rupture, and LV thrombus). Vaccines were developed quickly and were highly effective, but vaccines also can have cardiovascular complications including pericarditis, myocarditis, and thrombosis, in particular with younger patients and those with previous COVID-19 infection.

Gaps in knowledge

Although the response within the cardiovascular community to the COVID-19 crisis has been admirable, large gaps in knowledge remain: the ideal treatments for each stage of the disease; the appropriate timing of vaccines and boosters; the appropriate response to new viral variants; and the efficient adaptation of healthcare delivery for all patients. Clearly, there has been a substantial financial and psychological impact on cardiovascular training programs, cardiovascular practices, hospitals, and our patients. Perhaps the most challenging issue of all is the ongoing healthcare worker shortage, which includes all healthcare professionals including nurses and physicians, and which is most severe in high acuity-of-care settings, including the cardiac catheterization laboratory, surgical suites, and cardiac and other intensive care units.

Possible solutions and future directions

The Society for Coronary Angiography and Interventions (SCAI) has played a key role in the response to the COVID-19 pandemic in the United States in a number of important ways. Some of these include: (1) Surveys investigating the impact on interventional cardiology training programs, cardiac catherization laboratories, and interventional cardiology patients; (2) key position papers and guidelines, including an initial response regarding best practices for cardiac catheterization laboratories (published in March 2020³),and guidelines for the treatment of acute myocardial infarction (published in April 2020⁴), both of which have stood the test of time;³ (3) development of the North American COVID myocardial infarction (NACMI) registry (started in March 2020), which is now the largest registry for COVID patients with STEMI, and has provided unique insights into understanding this high-risk group;^5,6 (4) an online COVID-19 resource page for interventional cardiology practices; and (5) the “Seconds Still Count” public health campaign, designed to advocate to the population about the safety of both hospitals and physician offices, and encouraging patients to seek cardiovascular care quickly when needed. These efforts illustrate creative ways in which professional societies can respond to healthcare challenges like COVID-19. Still, in conclusion, we are likely not done with COVID-19 yet, and the cardiovascular community will need to continue to adapt.

References

1. Henry TD, Kereiakes DJ. The direct and indirect effects of the COVID-19 pandemic on cardiovascular disease throughout the world. Eur Heart J. 2022;43(11):1154-1156. doi:10.1093/eurheartj/ehab782

2. Atri D, Siddiqi HK, Lang JP, et al. COVID-19 for the cardiologist: basic virology, epidemiology, cardiac manifestations, and potential therapeutic strategies. JACC Basic Transl Sci. 2020;5(5):518-536. doi:10.1016/j.jacbts.2020.04.002

3. Welt FGP, Shah PB, Aronow HD, et al. Catheterization laboratory considerations during the coronavirus (COVID-19) pandemic: from the ACC’s Interventional Council and SCAI. J Am Coll Cardiol. 2020;75(18):2372-2375. Epub 2020 Mar 19. doi:10.1016/j.jacc.2020.03.021

4. Mahmud E, Dauerman HL, Welt FGP, et al. Management of acute myocardial infarction during the COVID-19 pandemic: a position statement from the Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Cardiology (ACC), and the American College of Emergency Physicians (ACEP). J Am Coll Cardiol. 2020;76(11):1375-1384. Epub 2020 Apr 21. doi:10.1016/j.jacc.2020.04.039

5. Garcia S, Dehghani P, Grines C et al. Initial findings from the North American COVID-19 Myocardial Infarction Registry. J Am Coll Cardiol. 2021;77(16):1994-2003. doi:10.1016/j.jacc.2021.02.055

6. Garcia S, Dehghani P, Stanberry L et al. Trends in clinical characteristics, management strategies and outcomes of STEMI patients with COVID-19. J Am Coll Cardiol. 2022;79(22):2236-2244. Epub 2022 Apr 4. doi:10.1016/j.jacc.2022.03.345

11.2 Disaster Preparedness for the Cardiovascular Service Line

Problem Presenter: Charles Brown, MD

Statement of Problem

The experience of COVID-19 is like nothing we have ever experienced before. The time interval from identification of the first case in Wuhan, China (December 31, 2019) until ­declaration of a “global pandemic” was 3 months (March 11, 2020). In the United States this interval was just 2 months (January 20, 2020-March 11, 2020), giving us little time to prepare for what was ahead. The initial phases of the pandemic were the most challenging for the healthcare system in the United States. At Piedmont Healthcare in Georgia, we were tasked with responding on a statewide level to what was to be an overwhelming medical crisis. We immediately established incident command centers and developed COVID testing protocols and processes, along with treatment, infection control, and prevention protocols. We were also challenged with determining both in-person and remote workforce requirements in response to isolation and “stay-at-home” orders issued by the federal government. Days seemed like years as most of this work was new to all of us, and was constructed on a daily basis as the world changed around us.

Interestingly, the Centers for Medicare and Medicaid Services (CMS) has an ­“Emergency Preparedness Rule,” but almost no healthcare system knew how to implement the recommendations, as they were built for single-hospital entities, and furthermore most of the responsive measures were designed for natural disasters and major trauma rather than pandemics. It was a new world order.

Gaps in knowledge

The “infrastructure” needed for a pandemic response was, and is, mostly unknown. Clearly, with the results of our recent experience, we know a lot more now than we used to know.  Most systems like ours brought together multidisciplinary teams at a Command Center to both develop and implement what was needed to care for our patients, our physicians, and our other staff.  These teams included members from administration, several medical subspecialties, including but not limited to infectious diseases, pulmonary and critical care medicine, primary care, and cardiology. We also had nursing, communications, human resources and staffing, supply chain, information technology, patient experience coordinators, and others. These teams met twice per day in the early days of the pandemic. Additionally, we established collaborative efforts with other healthcare systems in Georgia, with daily conference calls to compare notes on strategies developing within our respective institutions, all trying to share experiences and knowledge and coordinate our many efforts.

Possible solutions and future directions

The experience of COVID-19 has been a marathon and not a sprint. Outbreaks were not all occurring at the same time in different areas, some areas led and some lagged, even within the geography of our state. We also soon came to realize after the “first wave” that it was not over. At the time of this writing we have just passed our fifth surge, with a hopeful respite for a few months. The lessons have been profound, and it is safe to say that American medicine responded to the urgency at hand, and ultimately got control over the viral pandemic. Lessons learned were that while hospital-specific plans are good for a single entity, multihospital systems dealing with widespread events like a pandemic require a degree of coordination (“system-ness”) that demands a different kind of infrastructure. Now that we know this, we will have it in place for the next challenge. As the saying goes, “life as we knew it has changed forever.”

11.3 Censorship in Medicine: Politics in Science?

Problem Presenter: J. Jeffrey Marshall, MD

Statement of the problem or issue

Censorship in science and medicine is not new. In the 15th Century, the Catholic Church prevented certain medical books from being placed on library shelves, and had published periodically a list called “The Index” of the banned medical volumes. In the 21st Century, medical censorship has become much more complex due to improved methods of communication through increased numbers of medical journals, the internet, instantaneous television, printed news, and print or digital forms of social media. Censorship is defined as the suppression of words, images or ideas deemed as “offensive” or “absurd.” A close cousin of censorship is bias, defined as prejudice in favor of or against one idea compared with another in a manner considered unfair. Interestingly, different types of social media have been helpful as well as harmful in combatting scientific bias and censorship. Bias and censorship are antithetical to the scientific method which attempts to advance science through open dialogue, argument, and eventual proof or rejection of an hypothesis. Worse still, in today’s highly polarized world, politically motivated censorship is now even more prevalent, and was particularly evident during the recent pandemic.

One can view the spectrum of censorship in science and medicine as: (1) bias or censorship against new ideas; (2) bias or censorship against individual papers, procedures, or concepts; (3) bias or censorship against entire journals and communication channels; and (4) bias or censorship that is politically motivated in general.

An illustrative example of bias/censorship of a new idea is the saga of Dr Barry ­Marshall, a gastroenterologist (GI) in Australia who theorized that the bacterium H. Pylori was an etiologic agent causing gastric ulcer disease. The prevailing dogma at the time was that ulcer disease was due to cigarette smoking, stress, and alcohol consumption. Marshall’s hypothesis was considered “absurd” by prominent GI physician-scientists of the time, and his work gained no traction. He could not develop an animal model of ulcer disease to test his hypothesis, so after undergoing an upper endoscopy demonstrating no H. Pylori in his own gastric biopsies, Marshall then drank a slurry of broth containing H. Pylori bacteria. Very soon afterwards he developed biopsy-proven ulcer disease. It was only through a highly salacious form of social media at the time, Star Magazine, that would publish his story, as the “Human Guinea Pig Doctor.” This article in Star helped break through the censorship of his ideas and provide an outlet for his work. Ultimately, Marshall and his research partner, Dr Robin Warren, won the Nobel Prize in Medicine in 2005 for their seminal work on H. Pylori in gastric ulcer disease.

Likewise, the story of Dr Andreas Gruentzig is very similar to Dr Marshall, and much more recognizable in the cardiovascular field. However, some details of early bias against percutaneous transluminal coronary angioplasty (PTCA) are not as well known. While Dr Gruentzig’s successes in peripheral and even renal angioplasty were applauded and fairly well recognized, many of the prevailing cardiologists and angiologists believed the dogma that percutaneous angioplasty could never work in the heart. Gruentzig’s hypothesis that PTCA was safe and effective was felt by many to be “absurd.” His own Chief of Medicine hindered admission of patients to the hospital for the procedure, and his scientific papers were overly scrutinized—some would say reviewers were biased against his theory. Again, a highly sensational German publication, Schweizer Illustriete, with a cover page using a partially clad female model with body paint depicting a PTCA, highlighted the new procedure in paparazzi-type fashion. This article helped publicize the technique and Dr Gruentzig eventually overcame the bias and censorship against his novel procedure.

Another form of bias is levied against entire journals. In today’s world, the scientific method of discussion, with reasoned argument and evidence proving or refuting a proposed hypothesis, frequently occurs in an online forum facilitated through scientific journals. MedLine, the well-known medical search engine, has a literature selection committee that has the power to allow or prevent entry of any specific scientific journal into the MedLine registry. Certain general-interest periodicals like Time Magazine, which have very little or no original scientific content, are present on MedLine, while other serious scientific journals are excluded. One such excluded periodical is the Journal of Nutritional and Environmental Medicine, the official journal of the British, Australian, and American Societies for Ecological Medicine. This form of censorship is rather blatant, and it prevents new ideas in nutritional and environmental medicine from being discussed, referenced, or easily accessed by other physician-scientists.

During the COVID-19 pandemic, political polarization has resulted in outright bias and censorship regarding multiple scientific and medical issues. One example from Great Britain involved the scientific advisory group for emergencies (SAGE). The SAGE group had very few under-represented minorities involved in medical policy decisions. The SAGE group was aware that minorities and women had higher mortality rates from COVID-19, and yet these groups were not represented on the committee. Once again, social media, via a newspaper article, brought a shining light on this bias and the SAGE group was reconstituted with a more representative membership. In the United States, Senate hearings uncovered private emails of one government-employed epidemiologist who was attempting to discredit another “nonconforming” epidemiologist regarding interpretation of COVID-19 data. This type of government employee-based bias is quite concerning, due to inherent power gradients, and can be harmful to the scientific method and medicine.

Gaps in knowledge

First, censorship and bias are detrimental to application of the scientific method in medicine. However, how do we define scientific-medical bias and censorship for the purpose of combating them? In some instances, censorship and bias may operate quietly to suppress novel ideas. In the worst cases, novel ideas may be blatantly discouraged and it may even be professionally dangerous to support unconventional minority views on certain clinical topics or therapeutic procedures. With regard to politically based biases and censorship, totalitarian states have controlled their official narratives during the pandemic rather easily, but how should open democracies manage real or apparent biases without suppressing freedom of speech? Social media can be a powerful force in either direction, possibly protecting against biases and censorship, or alternatively, used as a weapon against “unfavored” minority opinions. How do scientists, countries, and societies in general monitor this powerful tool? Finally, and perhaps rhetorically, how can we keep politics out of science and medicine?

Possible solutions and future directions

Solutions likely will be very difficult, but we should not wait until the next pandemic or medical catastrophe before we begin attempts to solve the adverse influences of bias and censorship in science and medicine. We will not be able to keep politics from trying to enter medicine; therefore, we must change science and medicine so they can rise above bias and censorship. Medical societies are currently developing anti-bullying policies. Should they also develop anticensorship/antibias policies? In the examples cited above, social media was able to expose and change bias and censorship that was occurring in science and medicine by exposing it directly to the public. Finally, should peer-reviewed medical journals get into the business of communicating directly to the public in a manner similar to the direct-to-consumer medical advertising that we all experience daily in the media?

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Funding

These proceedings summarize the educational activity of the 16th Biennial Meeting of the International Andreas Gruentzig Society held January 31-February 3, 2022. These proceedings were funded in part by Abbott, Abiomed, Anteris, Boston Scientific, Canon, Chiesi USA, Inc, Cardiovascular Systems, Inc, EastEnd Medical, W.L. Gore, Medtronic, and Papilio Medical, Inc.

Physician Faculty List & Disclosure Summary

It is the policy of the International Andreas Gruentzig Society (IAGS) to insure balance, independence, objectivity, and scientific rigor in all its sponsored educational programs. All speakers, chairpersons, panelists and planning committee members participating in this program are expected to disclose to the program audience all potential conflicts of interest that might introduce a bias in their presentations.

The intent of this policy is not to prevent a participant with a potential conflict of interest from making a presentation. It is merely intended that any potential conflict should be identified openly so that the listeners may form their own judgments about the presentation with the full disclosure of the facts. It remains for the audience to determine whether the participant’s outside interests may reflect a possible bias in either the exposition or the conclusions presented.

The participants listed below have disclosed if they have any existing potential conflicts of interest with respect to their participation in our program:

J. Dawn Abbott, MD, FACC, FSCAI, Providence, RI, USA, Boston Scientific, Microport, CSL Behring: research with institutional compensation; Medtronic, Philips, Abbott, Recor: consulting with personal compensation.

Khaldoon Alaswad, MD, Detroit, MI, USA, Abbott CV, Asahi Intecc, Boston Scientific, CSI, LivaNova, Teleflex: consultant and speaker.

H. Vernon (Skip) Anderson, MD, FSCAI, Houston, TX, USA, nothing to disclose.

Salman Arain, MD, Houston, TX, USA, nothing to disclose.

Herbert Aronow, MD, MPH, FACC, FSCAI, FSVM, Providence, RI, USA, SilkRoad Medical: paid consultant, Clinical Events Committee (NITE trial); Philips: paid consultant, Data Safety and Monitoring Board (ILLUMENATE studies)

Steven Bailey, MD, MSCAI, San Antonio, TX, USA, Catheterization and Cardiovascular Interventions (CCI) : Editor in Chief.

Theodore Bass, MD, Jacksonville, FL, USA, nothing to disclose.

Itsik Ben-Dor, MD, Washington DC, USA, nothing to disclose.

Robert Bersin, MD, FACC, Seattle, Washington, USA, Ablative Solutions,  Omeros Corp, QT Vascular: equity interest; Boston Scientific: consulting relationship, equity interest, Proctor or Training Course Sponsorships; Cardiovascular Systems, Inc.: consulting relationship; Med Alliance; SA Advisory Board, equity interest; Medtronic Inc.: consulting relationship, Proctor or Training Course Sponsorships; Nectero Inc., Transverse Medical: advisory board, equity interest, stock options or positions.

Charles Brown III, MD, Atlanta, GA, USA, nothing to disclose.

Mauricio Cohen, MD, Miami, FL, USA, Terumo Medical, Zoll, Cordis, Merit Medical, Medtronic, Abiomed: consultant, Accumed Radial Systems: ownership.

Tyrone Collins, MD, FACC, New Orleans, Louisiana, USA, nothing to disclose.

Michael Cowley, MD, FSCAI, Richmond, VA, USA, nothing to disclose.

Abhijeet Dhoble, MD, Houston, TX, USA, Abbott Vascular, Edwards Lifesciences: consultant and Proctor.

Eric Dippel, MD, Davenport, IA, USA, nothing to disclose.

Tim Fischell, MD, FSCAI, Kalamazoo, MI, USA, Ablative Solutions, Inc., CrossLiner, Inc. Co-founder, shareholder, employee, royalties if and when commercialized. Angel Medical Systems, Inc: co-founder, shareholder, royalties when commercialized. Svelte Medical, Inc.: co-founder, royalties: Merit Medical, Inc, Cordis Corporation: royalties.

Kirk Garratt, MD, FSCAI, Stillwater, MN, USA, nothing to disclose.

Adam Greenbaum, MD, Atlanta, GA, USA, Edwards Lifesciences, Medtronic, Abbott: Honoraria; Transmural Systems: equity.

Cindy Grines, MD, Johns Creek, GA, USA, Abiomed, Philips: advisory board, Boston Scientific: Research Grant.

George Hanzel, MD, Atlanta, GA, USA Nothing to disclose.

Tarek Helmy, MD, FACC, FSCAI, Shreveport, LA, USA Nothing to disclose.

Timothy Henry, MD, FACC, MSCAI, Cincinnati, OH, USA, Neovasc: consultant (Reducer Trial)

Amir Lerman, MD, Rochester, MN, USA, nothing to disclose.

Victor (Sam) Lucas, Jr, MD, New Orleans, LA, USA, nothing to disclose.

Ayman Magd, MD, PhD, Cairo, Egypt, nothing to disclose.

J. Jeffrey Marshall, MD, Gainesville, GA, USA, Abiomed: Data Safety Monitoring Board.

Christopher Meduri, MD, Atlanta, GA, USA, Anteris: CMO; Boston Scientific, Vdyne, Cardiovalve, Alleviant, Abbott: consultant and speaking fees.

Michael Mooney, MD, FSCAI, Eden Praire, MN, USA, Nothing to disclose.

Jihad Mustapha, MD, Grand Rapids, MI, USA, BD Bard Peripheral Vascular, Cardiovascular Systems, Inc., Medtronic, Philips, Angiodynamics: Consultant; Boston Scientific, Terumo, PQ Bypass, Avinger: Consultant, Research; Micromedical Solutions: Consulting Chief Medical Officer (not employed), CardioFlow, Research, equity ownership.

Srihari Naidu, MD, FACC, FSCAI, Hawthorne, NY, USA, nothing to disclose.

Sigrid Nikol, Professor Dr. med., Hamburg, Germany, nothing to disclose.

E. Magnus Ohman, MD, Durham, NC, USA, Abiomed, Chiesi USA: Research; Cara Therapeutics, Cytokinetics, Milestone; Pfizer, Otsuka, Xylocor: consulting.

Brian O’Murchu, MD, Philadelphia, PA, USA, nothing to disclose.

William O’Neill, MD, FSCAI, Detroit, MI, USA, Abiomed, Abbott, Medtronic: consultant; Synchrony Labs: stock.

Rajan Patel, MD, New Orleans, LA, USA, Abiomed: speaker, advisory board; Boston Scientific, LevoNova: speaker.

Renato Ramos, MD, Royal Oak, MI, USA, nothing to disclose.

Michael Rinaldi, MD, Charlotte, NC, USA, Abbott Vascular: Speaker/consultant, teaching course, proctor, ad board, Case selection committee (Repair MR and Tendyne); Edwards: Speaker/consultant, proctor, ad board, Case Selection Committee (Pascal 2D/F); Boston Scientific: Speaker/consultant, research grant, ad board; 4C Medical: Case selection committee (AltaValve).

Gregory Robertson, MD, FACC, FSCAI, Atlanta, GA, USA, nothing to disclose.

Gary Roubin, MD, PhD, FSCAI, Birmingham, AL, USA, Cook, Inc.: royalties; Inspire MD: equity.

Carlos Sanchez, MD, Columbus, OH, USA, Medtronic: Proctor; Abbott Vascular: Medical Advisory Board/Speaker/Proctor; Boston Scientific: speaker; Edwards Lifesciences: speaker/proctor.

Janar Sathananthan, MBChB, Vancouver, British Columbia, Canada, Edwards Lifesciences, Medtronic: consultant, Research funding, NXT medical: consultant.

Binita Shah, MD, MS, New York, NY, USA, Philips Volcano: advisory board, Terumo Medical: consultant.

Fayaz Shawl, MD, FSCAI, Takoma Park, MD, USA, nothing to disclose.

Kimberly Skelding, MD, FACC, FAHA, FSCAI, Wenatchee, WA, USA, nothing to disclose.

Richard Smalling, MD, FSCAI, Houston, TX, USA, nothing to disclose.

Molly Szerlip, MD, Plano, TX, USA, Edwards Lifesciences: speaker consulting fee, CVI, SCAI, Boston Scientific: speaker honoraria.

Charles Thompson, MD, Zachary, LA, USA, nothing to disclose.

George Vetrovec, MD, MACC, MSCAI, Richmond, VA, USA, Abiomed: consultant.

Bonnie Weiner, MD. MSEC, MBA, Harvard, MA, USA, nothing to disclose.

B. Hadley Wilson, MD, Charlotte, NC, USA, nothing to disclose.

James Zidar, MD, FACC, FSCAI, Raleigh, NC, USA, Medtronic, advisory board.

Industry Members

George Adams, MD, MHS, FACC, Raleigh, NC, USA, Cordis: Chief Medical Officer.

Seth Bilazarian, MD, FACC, FAHA, FSCAI, Danvers, MA, USA, Abiomed, Employee.

Erik Davies, Flagstaff, AZ, USA, W. L. Gore & Associates, Inc., HCP Interactions Global Leader, Medical Products Division.

Regina Deible, Santa Clara, CA, USA, Abbott Vascular, Medical Science Manager.

Ryan Egeland, MD, PhD, MBA, St. Paul, MN, USA, Cardiovascular Systems, Inc., Chief Medical Officer.

Anthony Medigo, Miramar, FL, USA, East End Medical: Chief Commercial Officer, Transeptal Device, Siemens, Cardiovascular Systems: Formerly held Senior Management Positions.

Jay Meyer, Cary, NC, USA, Chiesi USA: Vice President – Business Unit Leader, Critical Care • Sales. 

Paul Puccioni, El Dorado Hills, CA, USA, Chiesi USA: Senior Director of Commercial Development.

Marvin Slosman, Tel Aviv, Israel, InspireMD, Chief Executive Officer.

David St. Denis, Eagan, MN, USA, Anteris Technologies Ltd., Chief Operating Officer.

Greg Walters, MBA, Malvern, PA, USA, Papilio Medical, Inc., CEO.

Nick West, MA, MD, FRCP, FACC, Santa Clara, CA, USA, Abbott, Chief Medical Officer & DVP, Global Medical Affairs, Vascular.

 

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