The future of interventional cardiology

Severe tricuspid regurgitation (TR) is known to be independently associated with adverse prognosis.1 Its importance is further emphasized by the prevalence of this entity, particularly in the aging population.2 Until the past few years, surgical management was the only available effective treatment for isolated severe TR. Operative mortality, nonetheless, remains high.3 Moreover, surgery is associated with a 45% recurrence rate after 5 years,4 and recent data suggest that surgery may not improve the survival rate in isolated severe cases of TR.5 Accordingly, guidelines recommend TR surgery as a class 1 indication only with concomitant left-sided valvular surgery.6 Conversely, patients with prohibitive surgical risk managed conservatively were shown to have dismal outcomes.7 Fortunately, the emergence of percutaneous devices expanded the horizon of TR treatment.

TACKLING THE MULTI-MECHANISTIC PATHOLOGY

TR is the product of various pathophysiological mechanisms including right ventricular (RV) dilatation with consequential leaflet tethering, tricuspid annular dilatation with subsequent mal-coaptation, atrial fibrillation causing further annular dilation through atrial enlargement, and abnormalities in the tricuspid valve leaflets and apparatus. At a certain point, regurgitation itself becomes an etiology through a vicious circle of RV and atrial remodeling. Accordingly, numerous percutaneous devices are being developed for transcatheter tricuspid valve repair (TTVr) and replacement (TTVR). They can be classified according to their mechanism—leaflet approximation, direct suture or ring annuloplasty and valve implantation that can be orthotopic—implantation in the anatomic tricuspid location or heterotopic implantation in the cavoatrial junction. The long-term stability of the orthotopic valve may be compromised due to the structural changes of the valvular apparatus over time that faces increased postoperative afterload. Some valves minimize this effect by not entirely relying on radial forces such as the Lux-Valve (Ningbo Jenscare Biotechnology, China) that attaches to the septum. Of note, a shortcoming of the Lux-valve is the thoracotomy requirement. An approach to relief RV pressure due to increased afterload is the Trisol valve (TriSol Medical, Israel) that induces leaflet coaptation by using a dome-shaped structure that enables larger RV closing volume. Additional orthotopic valves like the Intrepid (Medtronic, United States)—that received the Food and Drug Administration Breakthrough Device designation—and the Evoque (Edwards Lifesciences, United States) are showing encouraging results. Heterotopic valve implantation had been reported as double-valve implantation (inferior and superior vena cava), as well as single valve solely into the inferior vena cava. Nevertheless, the vena cavae can show substantial dynamic variations in size as well, particularly in self-expanding valves applying radial force on the compliant vessel, whereas right atrial enlargement can generate a funnel-shaped cavoatrial junction, thus increasing the risk of valve migration. Since the procedure results in the ventricularization of the right atrium, persistent overload can cause morphological changes and adversely impact the cardiac function.

Additional anatomical considerations play a role in device selection including the course of the right coronary artery, proximity to the atrioventricular node, and or/bundle of His (in this regard, the NaviGate valve—NaviGate Cardiac Structures, United States—has short graspers, and termed atrial winglets to prevent compression of the conduction system8), the dimensions of the inferior vena cava and its orientation relative to the right atrium (that can impact device stability and introduce difficulties achieving coaxiality), the size of the tricuspid annulus (large annuli may be modified as with the TriCinch—4Tech Cardio, Ireland—,9 that mimics the Kay procedure), the distance between the tricuspid annulus and the RV apex, the size of the iliac vein (eg, the Cardiovalve—Cardiovalve, Israel—and the Evoque utilize a relatively low profile), the presence of an intracardiac shunt, short leaflet length (with an insufficient grasping area), thickened nonpliable leaflets, coaptation gap and depth (usually over ~7mm is a predictor of leaflet approximation failure), tethering severity, the tenting area and height, the location of the regurgitant jet, the number of leaflets (eg, 3 or 4), a proper annular shelf, and the juxtaposed noncoronary sinus relative to the device anchoring to the anterior and septal leaflet commissures (that may be compromised by the anchoring mechanism).

Multiple factors must, therefore, be taken into observed when considering a patient for TTVr/TTVR, and a thorough evaluation is warranted. In advanced stages of the disease manifesting as severe RV enlargement, considerable tethering or very large annuli, TTVr and TTVR may not be technically feasible. The anatomical characteristics can exceed the device capabilities, eg, the maximum length of Cardioband (Edwards Lifesciences, United States) tricuspid system is 120 mm. Even if the intervention is technically possible with advanced disease, irreversible damage to the RV structure and function may impede clinical improvement. Nevertheless, the point of no return is not clear, and patients with RV dysfunction and pulmonary hypertension have the potential to improve.10

Finally, the patient’s characteristics must be reviewed as certain trials excluded patients with specific comorbidities like chronic kidney disease or systolic pulmonary artery pressure > 70 mmHg.

OUTCOMES OF PERCUTANEOUS TRICUSPID VALVE INTERVENTIONS

TriValve is the largest TTVr registry available predominantly describing edge-to-edge repair with MitraClip (Abbott Vascular, United States) in the tricuspid position. Use of MitraClip was described as bicuspidization of the tricuspid valve,11 by approximating the posterior or anterior leaflet to the septal leaflet (while anterior to the posterior leaflet clipping may distort the valvular apparatus). Devices operating with similar mechanisms are the TriClip (Abbott Structural Heart, United States), and the PASCAL (Edwards Lifesciences, United States).

Patients from studies describing the various devices were heterogenous and vary significantly from one to the other. Also, the 30-day mortality rate ranges from 0% to 13% with significant improvement in TR grade, and in the quality of life according to published data (table 1). Notable longer-term outcomes include a 20% mortality rate at 1-year follow-up in the MitraClip cohort,12 and a 26% mortality rate after 2 years in the Cardioband cohort.18 Currently, prospective efficacy data mostly rely on quality-of-life scores and TR grade. However, it was shown that patients with procedural failure have a significantly higher mortality rate,30 suggestive that patients would fare worse without the procedure. Moreover, a registry-based propensity-matched study that compared TTVr to conservative treatment showed symptomatic and survival benefits.31 Currently, 3 TTVr devices have received the CE marking: Cardioband, TriClip, and PASCAL system for the management of TR, but none have been approved by the U.S. Food and Drug Administration. Consequently, most percutaneous tricuspid interventions are applicable in trial settings or as compassionate use.

Table 1. Outcome data with transcatheter tricuspid valve devices

In conclusion, TTVR/TTVr devices are becoming considerably more viable options. Surgical, and most certainly, conservative treatment of patients with severe TR are not ideal choices and expanding treatment possibilities towards percutaneous approaches is, therefore, an obvious choice. Results from ongoing trials have been anticipated, which will hopefully be followed by the approval of additional devices.

FUNDING

None whatsoever.

CONFLICTS OF INTEREST

A. Latib has served on advisory boards or as consultant for Medtronic, Boston Scientific, Edwards Lifesciences, Abbott, and VDYNE. The remaining authors have no relations to disclose.

REFERENCES

Although mechanical reperfusion has been shown to achieve epicardial recanalization in almost all acutely occluded arteries, the optimal myocardial reperfusion still remains a major issue, and it is only achieved in barely 50% to 70% of the patients with ST- segment elevation myocardial infraction (STEMI).1 Several factors have been demonstrated to have an impact on myocardial reperfusion including preoperative Thrombolysis in Myocardial Infarction (TIMI) flow, ischemia time, ageing, diabetes, thrombus burden, and vessel size.1-3 Therefore, over the last few decades, several studies have been conducted on adjunctive therapies and devices to improve reperfusion such as antithrombotic therapies,4-5 and thrombectomy.6

The use of coronary stents, in particular drug-eluting stents, currently represents the standard of care,7 and considerable attention has been paid over the last decade on stenting techniques,8 and their impact on procedural results and outcomes.

In a paper recently published in REC: Interventional Cardiology, Vega et al.9 conducted a randomized trial to address the impact of the delivery system speed deflation on myocardial perfusion and the outcomes of patients with STEMI treated with direct stenting.

In fact, fast balloon deflation has been suggested to cause abrupt changes in coronary flow that may trigger the detachment of thrombotic material, and plaque fragments, disrupted by the stent strut coverage.10 Also, variations of intravascular pressure may increase the wall shear stress, which has been shown to promote plaque destabilization, endothelial dysfunction,11 and also the hydrostatic pressure inside the interstitial space favoring myocardial oedema, and cellular damage.12

Indeed, in post-conditioning strategies, balloon inflation has been proposed as a mechanism of protection against ischemic damage by inducing repeated sequences of ischemia-reperfusion that have been proven to reduce the infarct size.13

In a previous randomized study that recruited 211 patients, Gu et al.14 reported an improvement of coronary flow with the stent delivery system slow deflation strategy, yet with a not significant reduction of the no-reflow phenomenon, and null effects on the long-term outcomes.

However, this study primary endpoint was the corrected TIMI frame count, an index of coronary flow, whereas Vega et al.9 assessed the myocardial blush grade (MBG) and the ST-resolution, both parameters of myocardial perfusion that may be conditioned by several other factors.

In fact, the Spanish study9 was consistent with previous larger reports,8 and diabetes, hypertension, kidney disease, hemodynamic parameters, and lesion location emerged as independent predictors of MBG. Therefore, it may be argued that slow balloon deflation may have facilitated a successful epicardial reperfusion, although this did not translate into microcirculation differences or myocardial salvage.

Furthermore, although the extensive use of thrombectomy and glycoprotein IIb/IIIa inhibitors in the overall cohort of patients, as the authors very well pointed out, is not representative of the current guidelines-indicated strategies regarding primary percutaneous coronary intervention (PCI), it may have prevented such complications and minimized any potential benefits with the delivery system slow deflation strategy. Indeed, former studies and meta-analyses have demonstrated that the administration of these potent antiplatelet agents during a primary PCI, mainly as a downstream strategy,15 could translate into better myocardial perfusion, and reduce mortality.

In addition, the recruitment restriction to those lesions eligible for direct stenting in the study conducted by Vega et al.9 may have led to the selection of a very low-risk population where the occurrence of an impaired MBG was extremely low (observed in about 25% of the study population).

Finally, since the study was stopped after the recruitment of 50% of the predefined sample size for futility, we cannot discard that, with a larger population and different endpoints, any differences would have emerged. Future larger studies with a more heterogeneous and higher-risk population of patients with STEMI, more complex lesions, a higher rate of comorbidities, less extensive use of glycoprotein IIb/IIIa inhibitors, are certainly justified to better define the potential role of slow balloon deflation during primary PCI in terms of periprocedural complications, myocardial reperfusion, short- and long-term outcomes.

FUNDING

None whatsoever.

CONFLICTS OF INTEREST

None declared.

REFERENCES

Blood pressure indices like fractional flow reserve (FFR) and the instantaneous wave-free ratio (iFR) measure the distal-to-aortic pressure ratio of a lesion in a similar way using a pressure guidewire. FFR requires the induction of maximal hyperemia while the iFR is an index based on the assessment of pressure curves at rest. There is solid confirmation of the validity and efficacy of such indices from multiple studies while their use is widely backed by the clinical practice guidelines.1

However, the efficacy of blood pressure indices is based on 2 fundamental objectives. The first one is to prove that they are useful to indicate the revascularization of a lesion when the resulting value is below the cut-off point (≤ 0.80 for the FFR, and ≤ 0.89 for the iFR). The second one is to demonstrate that lesions with values above the cut-off point (> 0.80 or > 0.89, respectively) have a low risk of requiring revascularization, and lack of ischemic events at follow-up. Conceptually, the first indication is clear: a lesion with pathological values is an obstructive lesion that causes ischemia now. Therefore, if clinically indicated (and technically feasible) the best thing to do is to revascularize such a lesion. The second indication has a higher degree of uncertainty because a lesion that does not cause ischemia (now) does not necessarily mean that it will not cause it at some point in the future. This is so because the capacity of blood pressure indices (with normal results) to detect vulnerable plaques is limited, and they show a greater tendency towards progression or destabilization. Therefore, the negative predictive value of pressure indices is supposed to be worse when used in patients with a higher risk of progression into atherosclerotic cardiovascular disease.

Proof of this is that recent studies conducted in patients with acute myocardial infarction (AMI) and multivessel disease have demonstrated that the FFR of non-culprit lesions does not provide any clinical benefits regarding the revascularization of such lesions estimated visually and, therefore, under angiographic guidance.2,3 The prevalence of vulnerable plaques causing visual stenosis between 50% and 69% in non-culprit vessels of patients with AMI is estimated at around 30%. Actually this rate is probably higher when lesions with a greater degree of angiographic obstruction are studied.4 The COMBINE OCT-FFR trial also reported a similar rate of vulnerable plaques (25%) on the optical coherence tomography performed in diabetic patients with angiographic stenoses between 40% and 80% and normal FFR values.5 In this study, angiographic lesions with normal FFR values associated with vulnerable plaques had more adverse events (cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization) compared to those not associated with vulnerable plaques (13% vs 3%; P < .001).

The article by Castro-Mejía et al.6 recently published in REC: Interventional Cardiology provides the mid-term follow-up (3.5 years) of a large single-center registry of patients with intermediate angiographic lesions assessed using blood pressure indices and with normal results. This study compared the adverse events between diabetic and nondiabetic patients with the necessary statistical adjustments to compensate for the inherent differences of the baseline characteristics of both groups. The authors conclude that blood pressure indices (FFR and iFR) had a similar efficacy in diabetic and nondiabetic patients for not predicting future target vessel myocardial infarctions or the need for target lesion revascularization. However, we should mention that diabetic patients had higher rates of all-cause mortality, AMI, and need for revascularization compared to nondiabetic patients.6 We should specifically mention that there was a 2.6-fold higher risk of infarction in any vessels at the follow-up in diabetic compared to nondiabetic patients (P < .063 after adjustments). However, only 13% of the AMIs registered were adjudicated to the study vessel in diabetic vs 38% in nondiabetic patients.6 This difference can be due to chance alone or to the fact that the lesions that cause AMIs at the follow-up are scarcely susceptible to be studied with a pressure guidewire at the index procedure in diabetic patients. It is well known that these patients have more diffuse atherosclerotic cardiovascular disease, which complicates the correct angiographic assessment of the lesions (and, also, prevents the use of a pressure guidewire in such vessel for assessment purposes). It is highly likely that a strategy based on intravascular imaging modalities alone or in combination like in the COMBINE OCT-FFR trial can be of greater utility to detect this type of lesions.

Three recent studies have reported contradictory outcomes regarding the negative predictive value of blood pressure indices in diabetic patients. Kennedy et al.7 found more AMIs and a greater need for target lesion revascularization with normal FFR values in diabetic patients at the 3-year follow-up. On the contrary, Van Belle et al.8 found no differences between diabetic and nondiabetic patients who were deferred (for having normal FFR values) in 2 large registries conducted in Portugal, and France at the 1-year follow-up. No significant differences were seen either in the DEFINE-FLAIR substudy that analyzed adverse events between diabetic and nondiabetic patients in deferred patients at 1-year follow-up.9 It should be interesting to assess the long-term follow-up of these last 2 studies to see if the negative predictive value of blood pressure indices stays the same in diabetic and nondiabetic patients.

Finally, Castro-Mejía et al.6 propose that resting physiological indices with nonpathological findings may have a better negative predictive value compared to the FFR values of diabetic patients. This would be explained by the fact that one of the causes of discrepancy between the FFR and the iFR is microvascular dysfunction (that is more common in diabetic patients). Patients with microvascular dysfunction can have smaller drops of the pressure index during maximal hyperemia since not enough hyperemia is induced. However, resting physiological indices are not hyperemia-dependent, meaning that they should be more sensitive to detect significant epicardial lesions. However, this hypothesis was not confirmed by the DEFINE-FLAIR substudy on deferred diabetic patients.9

In conclusion, diabetic patients still remain as one of the challenges of interventional cardiology because they have more adverse events compared to nondiabetic patients (despite the proper optimal medical therapy). A more aggressive strategy to assess intermediate coronary lesions using pressure guidewires is advisable to guide complete revascularization in diabetic patients. Future studies should also assess whether a mixed strategy with intravascular imaging modalities of nonfunctionally significant arteries can be useful to prevent future events in this group of patients.

FUNDING

None whatsoever.

CONFLICTS OF INTEREST

J. Gómez-Lara has received speaking fees for presentations on behalf of Abbott Vascular, Boston Scientific, and Terumo. R. Romaguera declared no conflicts of interests whatsoever.

REFERENCES

The use of drug-eluting stents (DES) for the treatment of coronary artery stenosis substantially reduced the need for repeat revascularization compared to bare-metal stents.1 However, as many patients undergoing stenting have long life expectancy, and the incidence rate of stent failure increases with time since implantation, the number of patients presenting with DES restenosis is not insignificant and the treatment of these patients remains a challenge.2

Current clinical practice guidelines recommend treatment of restenosis associated with angina or ischemia by repeat revascularization with either repeat stenting with DES or angioplasty with drug coated balloon (DCB).3 Certain situations favour repeat stenting with DES, most notably loss of mechanical integrity of the restenosed stent. In general, however, although repeat stenting with DES may be more effective than angioplasty with DCB in the short-to-medium-term,4 avoidance of additional stent layers is an important consideration in the longer-term. Indeed, many centres prefer DCB angioplasty as a first-line approach for the treatment of restenosis in the absence of a compelling indication for repeat stenting.

The efficacy of DCB treatment relies on rapid transfer and subsequent tissue retention of the anti-proliferative agent, which is necessary for a persistent suppression of cell proliferation.5 Preclinical data suggest that micro-injuries to the vessel wall may enhance the ability of DCBs to inhibit neointimal growth.6 These micro-injuries can be achieved with a number of different types of modified balloon catheters, such as cutting or scoring balloons. Cutting balloon angioplasty is an attractive option thanks to its ability to effectively incise neointimal tissue and its ease of use.7 Scoring balloons are based on the same principle and may offer superior flexibility and deliverability at the expense of a somehow lower plaque disruption.

In a recent paper published in REC: Interventional Cardiology, Linares Vicente et al. reported on the 5-year results of cutting or scoring balloon angioplasty combined with DCB to treat in-stent restenosis.8 A total of 51 lesions (42 patients) were treated with cutting balloons plus DCBs, and 56 lesions (49 patients) with a standard DCB angioplasty. Both the SeQuent Please (B. Braun Melsungen AG, Germany), and the Pantera Lux (Biotronik, Switzerland) balloons were used. The primary endpoint was clinically driven target lesion revascularization at 5 years. It appears that, compared to the standard DCB strategy, the use of cutting or scoring balloons considerably reduced the 5-year rate of target lesion revascularization, although this difference was not statistically significant (9.8% vs 23.6%; odds ratio = 0.36; 95% confidence interval, 0.19-1.09; P = .05) (figure 1).

Figure 1. Target lesion revascularization (%): studies comparing cutting balloon/scoring balloon vs standard therapy in patients treated with percutaneous intervention for in-stent restenosis.

The study was retrospective and conducted at a single center with a small sample size of 91 patients. However, it is representative of real-world evidence, which may reflect clinical experiences across a broader and more diverse population of patients than those enrolled in randomized controlled trials. Regarding the baseline characteristics, almost 85% of patients were men with a mean age of 68.3 years. Patients had a high prevalence of diabetes mellitus and smoking (36% and 59%, respectively).

Interestingly, despite the current recommendations of the European Society of Cardiology,3 the use of intravascular ultrasound or optical coherence tomography was relatively low (5.9% in the cutting balloon group, and 8.9% in the standard group). Although this is consistent with rates observed in surveys of use in the clinical practice,11 it represents a missed opportunity for the mechanistic understanding of the disease etiology, and guidance for treatment optimization.12

The primary endpoint was the need for clinically driven target lesion revascularization at 5 years, which was 64% lower with cutting or scoring balloon angioplasty. Given the small sample size of this study and the relatively large treatment effect, it is a pity that insights from the angiographic follow-up were not available. Concordant data from systematic surveillance angiography would have given more confidence to the robustness of the observed treatment effect.

The results of this study should be interpreted in the context of earlier randomized controlled trials with cutting or scoring balloon angioplasty. In fact, evidence from such trials is scant including the RESCUT (Restenosis cutting balloon evaluation trial) trial9 published in 2003, and the more recent ISAR DESIRE 4 (Intracoronary stenting and angiographic results: optimizing treatment of drug-eluting stent in-stent restenosis 4) trial.10

In RESCUT, Albiero et al. randomized 428 patients with bare-metal stent in-stent restenosis across 23 European centers to receive either cutting balloon angioplasty or conventional balloon angioplasty.9 Overall, the trial showed neutral results: at late follow-up, the angiographic restenosis rate, minimal lumen diameter, and the rate of clinical events were similar in both arms (figure 1). Cutting balloon angioplasty, however, was associated with some important procedural advantages, such as use of fewer balloons, less requirement for additional stenting, and a significantly lower incidence of balloon slippage (6.5% vs 25%).

ISAR DESIRE 4 was a randomized, open-label, assessor-blinded trial that enrolled 252 patients with clinically significant DES restenosis undergoing DCB angioplasty at 4 different centres in Germany.10 This trial investigated scoring balloon rather than cutting balloon angioplasty. The primary endpoint–diameter stenosis at the 6-8-month follow-up angiography–was lower for the scoring balloon compared to the regular balloon angioplasty: 35% vs 40.4%; P = .047; in addition, target lesion revascularization was numerically lower (figure 1). Although, the size of treatment effect was modest, small incremental gains in efficacy in this challenging patient subset may translate into important clinical benefits.

Against this background, the observations made by Linares Vicente et al.8 are an important addition to the evidence supporting the clinical use of cutting or scoring balloons to treat stent failure. While repeat stenting with DES or angioplasty with DCB are the mainstay of in-stent restenosis procedures, the procedural efficiency and clinical efficacy of both approaches will likely improve with the adjunctive use of cutting or scoring balloons. The benefits of these devices are most likely mediated by a combination of factors: reduced balloon slippage (or watermelon-seeding), the mechanical advantage of increased disruption of restenotic tissue, and the potential for enhanced efficacy of the device-delivered drug. The management of patients with stent failure remains challenging and deserves the best treatment the operator can offer including the liberal use of cutting or scoring balloon lesion preparation. In this clinical setting, small margins can make a big difference.

FUNDING

L. McGovern is funded by the European Commission under the Horizons 2020 framework (grant agreement number 965246 CORE-MD).

CONFLICTS OF INTEREST

R.A. Byrne declared research or educational funding in the institution he currently works at from Abbott Vascular, Biosensors, Biotronik, and Boston Scientific. L. McGovern declared no conflicts of interest whatsoever.

REFERENCES