Article
Debate
REC Interv Cardiol. 2019;1:51-53
Debate: MitraClip. The heart failure expert perspective
A debate: MitraClip. Perspectiva del experto en insuficiencia cardiaca
aServicio de Cardiología, Hospital Clínico Universitario de Valencia, INCLIVA, Universidad de Valencia, Valencia, Spain bCIBER de Enfermedades Cardiovasculares (CIBERCV), Spain
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Debate: MitraClip. The interventional cardiologist perspective
QUESTION: What is the evidence available on the use of drug-coated balloons (DCB) in the de novo lesion setting?
ANSWER: The use of DCB to treat de novo lesions is the most compelling argument regarding this technology, an area that has advanced significantly over the last 5 years. Only recently, investigators and companies have begun to understand that this area also needed strong and reliable scientific evidence similar to the one provided for stent platforms, to understand the real safety and efficacy profile of DCB in the de novo lesion setting. Argument here is currently quite strong: the BASKET-SMALL 2 trial (700 patients) showed no differences at 3 years between paclitaxel-coated balloon and drug-eluting stents (DES),1 the EASTBOURNE (2100 patients) showed the 1-year safety and efficacy profile of the first sirolimus-coated balloon (target lesion revascularization, 5%),2 the PICCOLETO II trial3 showed fewer major adverse cardiovascular events with another paclitaxel-coated balloon compared to an everolimus-eluting stent in the small vessel setting at 3-year follow-up. Finally, the RESTORE SVD trial showed similar results with another paclitaxel-coated balloon at the long-term follow up and similar data vs DES.4 Interestingly enough, the long-term follow-up of the 2 latter trials was presented in September 2022 at the TCT Conference (late breaking clinical science session) confirming that this field is currently highly active.
Q.: Do you think there is enough evidence to recommend their use in the routine clinical practice?
A.: Evidence is compelling enough to recommend DCB in this setting. However, some simple rules should be applied a) we recommend using these devices in the in-stent restenosis setting under imaging guidance for proper lesion assessment. Therefore, treatment of small coronary vessels (< 2.5 mm) can be adopted. Afterwards, larger vessels should also be treated with DCB. The important thing here is to “have a good eye” to treat coronary artery dissections left after treatment (please see below); b) class effect does not exist for DCB. Therefore, only devices with robust clinical data should be used in this setting. Angiographic monitorization is often unnecessary unless DCB is used in a complex lesion setting without prior reliable experience or scientific evidence.
Q.: Do you think that there are differences in the results obtained from the studies and in the level of evidence according to the size of the target vessel?
A.: We believe that most DCBs can also be used for larger vessels (> 3 mm), but a wide use in this setting can be suggested in selected cases only where the stent is not seen as a safe enough solution (highly complex calcified lesions, trifurcations...). Also, the broader use of DCB requires more clinical data—that are still pending—which will hopefully be provided within the next 2 to 3 years. Unfortunately, direct comparisons among DCBs are not available yet except for a small, sponsored trial. A couple of years ago we “indirectly” compared a paclitaxel- and a sirolimus-coated balloon in the SIRPAC trial (1100 patients) showing no differences at 1 year regarding hard endpoints.5 The ongoing TRANSFORM I trial, which has recently completed the enrollment, is comparing paclitaxel- and sirolimus-based DCBs on mid-term angiographic and optical coherence tomography outcomes.6 This mechanistic study is important because it will shed light on the current effect of these drugs on the vessel wall, and on the role paclitaxel plays determining late lumen enlargement for a direct effect in the adventitia, something that is still to be proven by sirolimus. Finally, the ongoing TRANSFORM II trial that is comparing a sirolimus-based DCB to a DES will shed light on the long-term role of this technology.7 In this study, whose primary endpoint is TLF, patients with native vessel disease will be treated and followed for 5 years.
Q.: In which cases would you consider using DCBs to treat de novo coronary artery lesions?
A.: To be honest, given the drawbacks of stents in the small vessel disease and complex lesion settings, here a DCB would be our first choice due to the inherent safety of this technology. For example, in a heavily calcified coronary lesion, despite proper lesion preparation, we often prefer using a DCB when we are not totally sure that the stent will accommodate perfectly with an adequate expansion and apposition. The takeaway here is that DCBs can also lead to restenosis. However, they are safe and do not lead to thrombosis or acute vessel occlusion. Only in case of flow-limiting dissections or acute recoil, a bailout stent should be used after a DCB. Also, we should always remember that a stent-like result after DCB angioplasty should not be expected or is not needed either.
Q.: What is the predilatation protocol, cross-over criteria, and specific DCB treatment technique in this setting?
A.: This is a long topic of discussion, and dedicated courses should be followed to “have a good eye” on DCB angioplasty. Our initial suggestion is to adopt a stepwise approach when performing a DCB angioplasty, which means that the main goal is to achieve good results after proper predilatation with whichever tools are available at the cath lab. We can still cross over to a stent angioplasty at any time before drug delivery so make the final choice between DCB and DES after lesion preparation only. Proper predilatation means final stenosis < 30% and no major or flow-limiting dissections.8 After this goal is achieved, the DCB can be used to cover the entire segment treated while keeping inflation for, at least, 30 seconds (possibly 60). In our routine clinical practice we use semi-compliant balloons, and quite often scoring balloons, but other centers use non-compliant balloons as the first choice. The balloon-vessel ratio should often be 1:1, but exceptions exist depending on the target lesion. In the end, type A or B dissections should be sought, and not feared (figure 1). Our group has previously demonstrated how these dissections are safe and not associated with acute vessel occlusions.9 Recently, investigators from Japan have shown how dissections are associated with improved penetration and increased lumen gain at 6 months after paclitaxel-based DCB angioplasty.10 To be considered “expert” DCB users, stenting rate after DCB should be < 10%.
FUNDING
None whatsoever.
CONFLICTS OF INTEREST
None reported.
REFERENCES
1. Jeger RV, Farah A, Ohlow MA, et al. Long-term efficacy and safety of drug-coated balloons versus drug-eluting stents for small coronary artery disease (BASKET-SMALL 2): 3-year follow-up of a randomised, non-inferiority trial. Lancet. 2020;396:1504-1510.
2. Cortese B, Testa L, Di Palma G, et al. Clinical performance of a novel sirolimus-coated balloon in coronary artery disease: EASTBOURNE registry. J Cardiovasc Med (Hagerstown). 2021;22:94-100.
3. Cortese B, Di Palma G, Guimaraes MG, et al. Drug-Coated Balloon Versus Drug-Eluting Stent for Small Coronary Vessel Disease: PICCOLETO II Randomized Clinical Trial. JACC Cardiovasc Interv. 2020;13:2840-2849.
4. Tang Y, Qiao S, Su X, et al. Drug-Coated Balloon Versus Drug-Eluting Stent for Small-Vessel Disease: The RESTORE SVD China Randomized Trial. JACC Cardiovasc Interv. 2018;11:2381-2392.
5. Cortese B, Caiazzo G, Di Palma G, De Rosa S. Comparison Between Sirolimus- and Paclitaxel-Coated Balloon for Revascularization of Coronary Arteries: The SIRPAC (SIRolimus-PAClitaxel) Study. Cardiovasc Revasc Med. 2021;28:1-6.
6. Ono M, Kawashima H, Hara H, et al. A Prospective Multicenter Randomized Trial to Assess the Effectiveness of the MagicTouch Sirolimus-Coated Balloon in Small Vessels: Rationale and Design of the TRANSFORM I Trial. Cardiovasc Revasc Med. 2021;25:29-35.
7. Greco A, Sciahbasi A, Abizaid A, et al. Sirolimus-coated balloon versus everolimus-eluting stent in de novo coronary artery disease: Rationale and design of the TRANSFORM II randomized clinical trial. Catheter Cardiovasc Interv. 2022;100(4):544-552.
8. Cortese B. The role of optimal lesion preparation for de-novo coronary vessels when a stentless intervention strategy is planned. Minerva Cardioangiol. 2020;68:51-56.
9. Cortese B, Silva Orrego P, Agostoni P, et al. Effect of Drug-Coated Balloons in Native Coronary Artery Disease Left With a Dissection. JACC Cardiovasc Interv. Dec 2015;8:2003-2009.
10. Yamamoto T, Sawada T, Uzu K, Takaya T, Kawai H, Yasaka Y. Possible mechanism of late lumen enlargement after treatment for de novo coronary lesions with drug-coated balloon. Int J Cardiol. 2020;321:30-37.
QUESTION: What aspects do you think might explain the significant differences reported between the results from the EBC MAIN (European bifurcation club left main coronary stent study),1 and the DKCRUSH-V (Double kissing crush vs provisional stenting for left main distal bifurcation lesions) clinical trials?2
ANSWER: The EBC MAIN trial has proven the non-inferiority of the step-by-step provisional stenting technique approach compared to the early double stenting strategy in 467 patients with distal left main coronary artery bifurcation disease (Medina 1,1,1 or 0,1,1). No significant differences were reported regarding the overall rate of major adverse cardiovascular events, target lesion failure, acute myocardial infarction, and stent thrombosis.1
On the other hand, the DKCRUSH V trial randomized 482 patients with distal left main coronary artery bifurcation disease (Medina 1,1,1 or 0,1,1) to receive treatment with the provisional technique vs the DK-crush technique. The latter had a lower rate of major adverse cardiovascular events with statistically significant differences regarding target lesion failure (10.7% vs 5%) (hazard ratio, 0.42; 95% confidence interval, 0.21-0.85; P = .02), acute myocardial infarction (2.9% vs 0.4%; P = .03), and stent thrombosis (3.3% vs 0.4%; P = .02) at 1-year follow-up.2 Results were better in the most complex coronary bifurcation lesions defined, above all, as those with greater side branch damage (> 70% of stenosis and > 10 mm of lesion length), severe calcification or well-defined angles (> 70 or < 45º).
Some have tried to compare data from the EBC MAIN to data from the DKCRUSH-V. However, there are aspects that just don’t make them comparable trials for study design reasons or for the overall results of the DK-crush technique: the complexity of bifurcation and the degree of damage to the side branch was lower in the EBC MAIN compared to the DKCRUSH-V defined by severity of stenosis > 70% and length > 10 mm. As a matter of fact, the mean side branch lesion length was 7 mm in the EBC MAIN vs 16 mm in the DKCRUSH-V, which can be seen in the rate of double stenting of the provisional group (22% in the EBC-MAIN vs 47% in the DKCRUSH-V). Similarly, the low rate of double stenting of the provisional group was left to the operator’s criterion allowing residual lesion in the ostial left circumflex artery of 90% vs 75% in the DKCRUSH-V. In my opinion, another factor penalizing the double stenting group is that only 5% of the patients were treated with the DK-crush technique since the most widely used ones were the culotte (53%), and the T or TAP (T and protrusion) techniques (33%). Also, 6% of the patients from the double stenting group could not receive the second stent unlike the DKCRUSH-V trial where the procedural success of the DK-crush group was 100%. The use of imaging modalities in both studies was similar in around 40% of the cases.3
Q.: In the light of the evidence available and based on your own experience, when do you recommend provisional stenting and when an early double stenting technique to treat distal left main coronary artery stenoses?
A.: Obviously, the only lesions eligible for 2-stent implantation into the distal left main coronary artery are those found in bifurcations we call complex or true bifurcations, that is, when both left main coronary artery branches are damaged (Medina 1,1,1 or 0,1,1). However, among these lesions, the complexity of left main coronary artery bifurcation lesions depends on many different factors, among them, the DEFINITION II trial criteria are the most widely used of all. As far as I know, they’re the most important ones of all regarding the selection of the bifurcation technique that will eventually be used: simple or complex (left main coronary artery bifurcation with side branch stenosis > 70% and lengths > 10 mm, moderate-to-severe calcifications, bifurcation angles < 45º or > 70º, multiple lesions, main vessel reference diameters > 2.5 mm, main vessel lesion lengths > 25 mm or presence of thrombus in the lesion).4
This trial proved that complex bifurcations, under these criteria, are associated with fewer events if treated with the complex double stenting technique compared to the provisional stenting technique. In my opinion, the most valuable criteria that should be used when having to decide between provisional or complex stenting techniques—rather than the severity of stenosis in the side branch—are side branch lesion lengths > 10 mm, moderate-to-severe calcifications, and bifurcation angles < 45º. Angles > 70º can be solved much easier using the provisional 1-stent technique with minimal protrusion in bailout T or TAP.
Q.: In how many angioplasties performed on the distal left main coronary artery is the double stenting technique often used?
A.: Provisional stenting technique used systematically is valid to treat most distal left main coronary artery disease including true bifurcations with side branch damage, assuming that 20% to 40% of the patients will end up with a second stent in the side branch. At our center, however, there are patients we directly treat with 2 stents for being high-complexity patients. The rate of left main coronary artery true bifurcations is somewhere between 25% and 30%.
Q.: What is your favorite double stenting technique in the distal left main coronary artery and why?
A.: I’d say scientific evidence is rather clear on what the double stenting technique of choice should be to treat complex distal left main coronary arteries. In addition to the aforementioned results from the DKCRUSH-V and the DEFINITION II trials where 77.8% of the patients treated with 2 stents received the DK-crush technique,1,4 2 meta-analyses recently published have confirmed the superiority of the DK-crush technique vs other bifurcation techniques. In the one conducted by Di Gioia et al.5 of a total of 5711 patients, 5 different bifurcation techniques used in the studies were compared (provisional stenting, T-stent, TAP, crush, culotte, and DK-crush). It was found that patients treated with the DK-crush technique had lower rates of major adverse cardiovascular events, significant differences regarding the need for new target lesion revascularization (odds ratio, 0.36; 95% confidence interval, 0.22-0.57), and no differences regarding cardiac death, myocardial infarction or stent thrombosis. The biggest clinical benefits from using the DK-crush technique were reported in lesions with side branch disease > 10 mm in length, that is, the most complex bifurcations of all. The second meta-analysis conducted this year by Park et al.6 after the publication of the EBC MAIN results—with a total of 8318 patients—reached the same conclusions. In the conventional meta-analysis, the DK-crush technique proves non-superior to the provisional stenting technique except for cases with side branch disease and lengths > 10 mm where there is a lower rate of cardiac death, and target vessel revascularization. However, when a multiple comparison analysis was conducted, the DK-crush technique had a lower rate of major adverse cardiovascular events regarding cardiac death, acute myocardial infarction, target vessel revascularization, and stent thrombosis compared to the provisional stenting technique and any other double stenting technique including T-stent, TAP, dedicated bifurcation stents, crush, and cullote.6
Among the complex double stenting techniques, the culotte one is a very flexible technique we can use to choose the branch we want to treat first, the main vessel or the side branch. Recently, changes have been made that improve its result by minimizing stent overlap in the main vessel and adding a first kissing balloon (KB) after the first stent implantation (DK-mini-culotte) thus improving stent comformability at bifurcation level and improving the success rate of the final KB.7 However, we still don’t have any evidence on the results of the DK-crush technique.
Despite the results published with the DK-crush technique, it has not become the technique of choice in most centers because it is technically very challenging since 8 very well-defined steps are involved that can’t be omitted since the technique needs to be refined in every step of the way. However, the main setback of this technique is that it is very much time-consuming. Also, the material needed is often unusual and without proper optimization, which means that it can jeopardize results in the real-world. Early POT (proximal optimization technique) is very important here, also KB with non-compliant high-pressure balloons, and final POT. Similarly, the technique needs to be refined based on the recommendations established in the EBC MAIN trial regarding POT, and the KB.
Finally, since this is a time-consuming and challenging technique that takes up a lot of resources, changes to this technique to optimize results and improve procedural times are almost non-stop. One of them is high-pressure stent postdilatation of the side branch at ostial level (proximal SB optimization) that improves stent comformability at carina level and facilitates later recrossing.8 The other one is the DR-crush (double rewire crush) technique that facilitates sequential dilatation of the side and main branches thus avoiding early KB, which simplifies the entire procedure with very good results at 2 years.9
Q: In your opinion, do you think that the use of intravascular imaging modalities to guide these procedures on the left main coronary artery is important?
A: I believe we all agree that the use of imaging modalities to treat these bifurcation lesions at the left main coronary artery is mandatory to both plan the strategy that should be followed and assess the final outcomes. It is the only way to offer the best possible results in a lesion of such prognostic impact. Regarding the most appropriate technique, I think it should be the one the operator is more familiar with. Although it is true that intravascular ultrasound has gained traction to treat the left main coronary artery, since distal segment is involved and as long as we’re not dealing with short left main coronary arteries or excessively large calibers preventing good contrast, the optical coherence tomography would also be useful thanks to its high spatial resolution.
FUNDING
None reported.
CONFLICTS OF INTEREST
None whatsoever.
REFERENCES
1. Hildick-Smith D, Egred M, Banning A, et al. The European Bifurcation Club Left Main Coronary Stent study: a randomized comparison of stepwise provisional vs. systematic dual stenting strategies (EBC MAIN). Eur Heart J. 2021;42:3829-3839.
2. Chen SL, Zhang JJ, Han Y, et al. Double Kissing Crush Versus Provisional Stenting for Left Main Distal Bifurcation Lesions: DKCRUSH-V Randomized Trial. J Am Coll Cardiol. 2017;70:2605-2617.
3. Jaffer HFA, Mehilli J, Escaned J. Left main coronary disease at the bifurcation: Should the pendulum swing back towards the provisional stenting approach? Eur Heart J. 2021;42:3840-3843.
4. Zhang JJ, Ye F, Xu K, et al. Multicentre, randomized comparison of two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: the DEFINITION II trial. Eur Heart J. 2020;41:2523-2536.
5. Di Gioia G, Sonck J, Ferenc M. Clinical Outcomes Following Coronary Bifurcation PCI Techniques: A Systematic Review and Network Meta-Analysis Comprising 5,711 Patients. JACC Cardiovasc Interv. 2020;13:1432-1444.
6. Park DY, An S, Jolly N, et al. Systematic Review and Network Meta-Analysis Comparing Bifurcation Techniques for Percutaneous Coronary Intervention. J Am Heart Assoc. 2022;11:e025394.
7. Toth GG, Sasi V, Franco D, et al. Double-kissing culotte technique for coronary bifurcation stenting. EuroIntervention. 2020;16: e724-733.
8. Lavarra F. Proximal side optimization: A modification of the double kissing crush technique. US Cardiology Review. 2020;14:e02
9. Zhang D, He Y, Yan R, et al. A novel technique for coronary bifurcation intervention: Double rewire crush technique and its clinical outcomes after 2 years of follow-up. Catheter Cardiovasc Interv. 2019;93(S1):851-858.
QUESTION: What aspects do you think might explain the significant differences reported between the results from the EBC MAIN (European bifurcation club left main coronary stent study),1 and the DKCRUSH-V (Double kissing crush vs provisional stenting for left main distal bifurcation lesions) clinical trials?2
ANSWER: Both studies differ in several aspects we could categorized into 4: those that are operator-related; study design-related; patient and lesion-related, and those associated with the results from the provisional stenting technique.
The double kissing (DK) is a complex technique where most of the evidence available in the medical literature (including the DKCRUSH-V2) comes from the same group of expert operators who have been using such technique for years now.3,4 However, the operators from the EBC MAIN1 belong to the European Bifurcation Club that has spent years promoting and refining the provisional stenting technique.
Regarding the study design, the group of patients randomized to 2 different stents is also different from one trial to the other: in the DKCRUSH-V only patients treated with the DK crush technique were while in the EBC MAIN most patients were treated with the culotte technique or the T stenting technique. Another different aspect between both trials is the use of systematic angiographic assessments at 1-year in the DKCRUSH-V trial (66% of the patients). It is precisely at this point when event curves separate, and significant differences arise. This strategy can introduce a bias in the study in favor of the double stenting technique that has better angiographic appearance.
The type of patients included is also different and can condition the results. The SYNTAX score was different between both studies being more complex the lesions of the of all DKCRUSH-V trial (31% vs 23%). Also, the length of the lesion in the collateral branch (usually the left circumflex artery) turned out to be longer in the DKCRUSH-V trial: 16 mm vs 7 mm. Therefore, these bifurcations with very long lesions in the side branch penalize the provisional stenting group.
Another aspect that calls our attention in the group of patients randomized to the provisional stenting technique in the DKCRUSH-V trial are the poor results obtained in this group. These results compare to the experience of many other groups and the results obtained on the EBC MAIN trial. Therefore, the rate of stent thrombosis (acute/subacute) in this group is high (2.5%) compared to the 0.8% reported from the EBC MAIN provisional stenting technique group. Also, the crossover rate to 2 stents is the highest of all in the provisional stenting group of the DKCRUSH-V trial compared to the EBC MAIN (47% vs 22%). These differences could be associated with the type of complexity of bifurcation (more complex in the DKCRUSH-V study).
Q.: In the light of the evidence available and based on your own experience, when do you recommend provisional stenting and when an early double stenting technique to treat distal left main coronary artery stenoses?
A.: According to the DKCRUSH-V trial2 and a meta-analysis recently published,3,4 if the provisional stenting technique does not give good results in complex bifurcation the recommendation of using «complex techniques (2 elective stents) for complex bifurcations» can be accepted. The problem consists of identifying this type of unfavorable bifurcations for a simple strategy. The DEFINITION trial (Definitions and impact of complex bifurcation lesions on clinical outcomes after percutaneous coronary intervention using drug-eluting stents)5,6 proposes a score based on 2 major criteria and 6 minor ones to distinguish simple from complex bifurcations. On the contrary, such meta-analysis3 identifies patients eligible who would benefit from the DK-Crush technique much easier: patients with long lesions > 10 mm in the collateral branch.
I’m more inclined towards easy rules and I’d make a slight modification of the Medina classification7 by adding, at the end, a letter based on the length of the collateral branch: S (short) < 10 mm, and L (long) > 10 mm. Therefore, we’d be recommending the provisional stenting strategy in the presence of these bifurcations:
- • 1, 1, 1, S
- • 1, 0, 1, S
- • 0, 1, 1, S
- • 1, 1, 0
- • 0, 1, 0
- • 1, 0, 0
However, in the following types of bifurcation we’d rather use the double stenting technique:
- • 1, 1, 1, L
- • 1, 0, 1, L
- • 0, 1, 1, L
Special situations like bifurcations with wiring of the collateral branch are difficult or restenosis of a simple technique can also be considered indications for the use of the elective double stenting technique in the bifurcation.
Q.: In how many angioplasties performed on the distal left main coronary artery is the double stenting technique often used?
A.: As a matter of fact, I think that we’d be under the numbers reported in the EBC MAIN trial (around 10%). For example, in our participation in the OPTIMAL trial of 21 patients included to this date with left main coronary artery disease, none of them was treated with the double stenting technique.
Q.: What is your favorite double stenting technique in the distal left main coronary artery and why?
A.: According to the data published in the medical literature available, I’d have to say the DK crush technique since it’s the most favored of all in the comparative studies conducted.3 However, such studies have the limitations already mentioned here.4 In its latest consensus document, the European Bifurcation Club8 recommends the provisional stenting technique when planning to use 1 single stent. Also, when the use of 2 stents can be anticipated before the procedure. In my opinion, the T stenting technique is the best one when the left main coronary artery/left circumflex artery has a configuration of 90º more or less. In such a way that the implantation of the second stent can be performed precisely into the ostium of the collateral branch by covering it completely without causing significant invasion of the carina. In case of a narrower angle, the DK-culotte technique would be the preferred one since it is impossible to make a perfect adjustment of the second stent without invading the main vessel or leaving a space without «stenting» the collateral branch. This technique can be used starting with the main vessel (provisional stenting philosophy) or the collateral branch (inverted culotte). The most practical thing to do would be to start with the diseased branch and then move on with a combo of POT (proximal optimization technique) plus double kissing balloon. This technique has been described recently,9 and we don’t have comparative studies against the DK crush technique. However, when refined8 it achieves an excellent stent expansion and apposition across all the bifurcation segments, which should lead to clinical outcomes.
Q: In your opinion, do you think that the use of intravascular imaging modalities to guide these procedures on the left main coronary artery is important?
A.: The use of intravascular imaging—mainly the intravascular ultrasound (IVUS)—in the percutaneous treatment of left main coronary artery has been a constant recommendation over the last few years.10,11 However, this recommendation is only based on the opinion of experts and observational studies. Therefore, in the latest European guidelines12 the recommendation of using IVUS in the percutaneous management of the left main coronary artery is weak (only IIa B). To achieve recommendation I, a randomized clinical trial would be needed to confirm that there are fewer clinical events. That is the objective of the OPTIMAL trial we are involved with right now. Although a study of this magnitude could change the clinical guidelines, the recruitment of patients is sometimes difficult to see because of our conviction that IVUS is necessary to perform stenting properly, and operators don’t want to leave randomized patients away from the benefits the technique has to offer. By describing this problem we face on a daily basis at the cath lab I think I have already answered to this question.
FUNDING
None whatsoever.
CONFLICTS OF INTEREST
Conference or workshop minor fees from Abbott, Boston, Phillips, and Worldmedica have been declared.
REFERENCES
1. Hildick-Smith D, Egred M, Banning A, et al. The European Bifurcation Club Left Main Coronary Stent study: a randomized comparison of stepwise provisional vs. systematic dual stenting strategies (EBC MAIN). Eur Heart J. 2021;42:3829-3839.
2. Chen SL, Zhang JJ, Han Y, et al. Double Kissing Crush Versus Provisional Stenting for Left Main Distal Bifurcation Lesions: DKCRUSH-V Randomized Trial. J Am Coll Cardiol. 2017;70:2605-2617.
3. Di Gioia G, Sonck J, Ferenc M, et al. Clinical outcomes following coronary bifurcation PCI techniques: a systematic review and network meta-analysis comprising 5,711 patients. JACC Cardiovasc Interv.2020;13:14321444.
4. Pan M, Ojeda S. Complex Better Than Simple for Distal Left Main Bifurcation Lesions. Lots of Data But Few Crushing Operators. JACC Cardiovasc Interv. 2020;13:1445-1447.
5. Chen SL, Sheiban I, Xu B, et al. Impact of the complexity of bifurcation lesions treated with drug-eluting stents: the DEFINITION study (Definitions and Impact of Complex Bifurcation Lesions on Clinical Outcomes After Percutaneous Coronary Intervention Using Drug-Eluting Stents). JACC Cardiovasc Interv. 2014;7:1266-1276.
6. Zhang JJ, Ye F, Xu K, et al. Multicentre, randomized comparison of two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: the DEFINITION II trial. Eur Heart J. 2020;41:2523-2536.
7. Medina A, Suárez de Lezo J, Pan M. Una clasificación simple de las lesiones coronarias en bifurcación. Rev Esp Cardiol. 2006;59:183.
8. Lassen JF, Albiero R, Johnson TW, et al. Treatment of coronary bifurcation lesions, part II: implanting two stents. The 16th expert consensus document of the European Bifurcation Club. EuroIntervention. 2022;18:457-470.
9. Toth GG, Sasi V, Franco D, et al. Double-kissing culotte technique for coronary bifurcation stenting. EuroIntervention. 2020;16:e724-e733.
10. Burzotta F, Lassen JF, Banning AP, et al. Percutaneous coronary intervention in left main coronary artery disease: the 13th consensus document from the European Bifurcation Club. EuroIntervention. 2018;14:112-120.
11. Mintz GS, Lefèvre T, Lassen JF, et al. Intravascular ultrasound in the evaluation and treatment of left main coronary artery disease: a consensus statement from the European Bifurcation Club. EuroIntervention. 2018;14:e467-e474.
12. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. ESC Scientific Document Group. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019;40:87-165.
QUESTION: What types of catheter-based invasive approaches are available today to treat acute pulmonary thromboembolism? Please give us a brief description of the techniques used.
ANSWER: Catheter-directed therapy (CDT) to treat pulmonary thromboembolism falls into 3 different categories: mechanical thrombectomy, local thrombolysis, and a combination of both.
Mechanical thrombectomy (MT) consists of thrombus fragmentation, aspiration or removal. Fragmentation consists of using CDT nonspecific devices such as pig-tail catheters (forced rotation inside the thrombus) or dilatation balloons to break down and fenestrate the thrombotic occlusion to improve flow towards completely occluded regions. This technique is not very precise or reproducible so as new specific devices appear it will probably fall into oblivion. It is often used as an early facilitator of aspiration or penetration of the thrombolytic drug. Thrombus aspiration or removal consists of using hollow catheters of different calibers to aspirate the thrombus. This technique is highly dependent on the age the thrombus (more effective the more acute the case is) and the caliber of the aspiration catheter. Nonspecific material for coronary interventions (guide catheters of up to 8-Fr) or structural or peripheral heart procedures can be used (long introducers or sheaths > 8 Fr), with the advantage of its wide availability and low prices; the setback, however, is that the catheter usually becomes occluded, which is why it is often used in double ‘mother-and-child’ systems.
Also, there are 2 aspiration devices that have been specifically approved to treat PTE: the Indigo system (Penumbra, United States), a 115 cm 8-Fr angled tipped catheter with an olive-shaped burr to facilitate the entry and advancement of the thrombus, which will soon will be available in 12-Fr,1 and the FlowTriever system (Inari Medical, United States), specifically designed for PTE aspiration, and including a 24-Fr catheter, a 16-Fr guide catheter extension system, and a nitinol disc-shaped thrombus retriever. Its main advantage is that its outside connections are oversized at larger diameters compared to the Luer medical device standard.2 The Nautilus—a 10-Fr catheter system from iVascular, Spain—is currently in the pipeline. Other peripheral thrombectomy non-specific PTE devices like AngioVac (Angiodynamics, United States) or AngioJet (Boston Scientific, United States) are less common since more complications have been reported.
Compared to local thrombolysis, the advantages of MT by strong aspiration are that it can facilitate the patients’ rapid hemodynamic improvement, also ending in a single procedure that can prevent the use of fibrinolytic agents when used as monotherapy.
Local thrombolysis (LT) consists of introducing 1 or 2 usually multiperforated catheters into the pulmonary artery and in the intra-thrombus position through which 1 variable dose (around 25% of the systemic dose) of a fibrinolytic agent (often rt-PA) is introduced for a certain time (6 h to 24 h) with or without an initial bolus. Its main advantages are that it is easy to use, the possibility of using peripheral vascular access (antecubital vein or veins), and its low cost (a pig-tail catheter can be used). There is an ultrasound-facilitated LT (UFLT) device manufactured by EKOS (Boston Scientific, United States) that comes with a catheter with multiple ultrasound pulse generators to facilitate the fragmentation the fibrin threads while improving drug penetration into the thrombus.
Finally, the combination of MT1 plus LT is based on the principle that MT can act upon the most proximal segments of pulmonary and lobar branches while LT can later act upon lower caliber branches in the entire pulmonary tree.
Q.: What is the clinical evidence available on intravascular thrombolysis and thrombus aspiration therapies?
A.: Most historic evidence on CDT comes from registries and case series. However, over the last few years, the development of specific devices has produced new and high-quality pieces of evidence. There are still gaps of knowledge on the use of CDT to treat high-risk PTE (scarce and heterogeneous data), and comparative data on the different CDT techniques available.
Several registries prior to the development of specific devices like the PERFECT showed, for the very first time, better clinical outcomes with low rates of bleeding too. A meta-analysis of multiple trials on CDT conducted over the last decade provides aggregate data of 1168 patients showing overall rates of procedural success (95% confidence interval [95%CI], 72.5-89.1%), 30-day mortality (95%CI, 3.2-14.0%), and major bleeding (95%CI, 1.0-15.3%) of 81.3%, 8.0%, and 6.7%, respectively, in high-risk PTE. In intermediate-risk PTE, the rates of procedural success (95%CI, 95.3-99.1%), 30-day mortality (95%CI, 0%-0.5%), and major bleeding (95%CI, 0.3-2.8%) were 97.5%, 0% and > 1.4%, respectively.4
MT (aspiration) with the Indigo device was included in the single arm EXTRACT-PE clinical trial5 of 119 patients with intermediate-risk PTE. The efficacy (a 0.43 reduction in the right ventricle/left ventricle (RV/LV) ratio at 48 hours) and safety profile (rates of major bleeding, and intracranial hemorrhage of 1.7%, and 0%, respectively) was confirmed in a protocol with almost non-use of LT (98.3%). The FlowTriever device was used to conduct the FLARE trial6 of 106 intermediate-risk patients treated without thrombolytic drugs. The device proved its efficacy (a reduction of 0.38 in the RV/LV ratio at 48 hours) and safety profile (rates of major adverse events, major bleeding, and intracranial hemorrhage of 3.8%, 1%, and 0%, respectively). These results were confirmed in the first 250 patients of the FLASH registry7 with a rate of major adverse events of 1.2% (3 hemorrhages, none of them intracranial).
The EKOS device was studied in the ULTIMA randomized clinical trial8 of 59 patients with acute intermediate-risk PTE and a RV/LV ratio > 1 who were randomized to receive fixed doses of rt-PA (10 mg or 20 mg in bilaterals) in UFLT. It confirmed further reductions of the RV/LV ratio at 24 hours compared to standard therapy with heparin (mean reduction of 0.30 ± 0.20 vs 0.03 ± 0.16 (P < .001). The SEATTLE II registry9 of 150 patients most of them with submassive PTE demonstrated a similar efficacy profile with reasonable safety data (rates of 30-day major bleeding and intracranial hemorrhage of 10% and 0%, respectively).
The only comparative randomized clinical trial published to this date of 2 CDT strategies is the SUNSET sPE10 that found no differences in the radiologic thrombus load reduction with UFLT or simple LT with similar doses of thrombolytic drugs.
Q.: What are today’s indications for invasive treatment and how does the routine clinical practice at your center look like?
A.: In the clinical practice guidelines published by the European Society of Cardiology in 2019, CDT is given an indication IIa, level of evidence C, for patients with high-risk PTE in whom systemic thrombolysis (ST) is contraindicated or in cases when it has failed. Also, these guidelines rank CDT as an alternative to ST as a bailout therapy in patients initially treated with anticoagulation (often intermediate-high-risk PTE) with hemodynamic impairment (indication IIa, level of evidence C).
The alternative to CDT with a similar indication but a higher level of recommendation (indication I – level of evidence C) is surgical embolectomy. However, the availability of surgical teams ready to operate on these patients is very limited, as well as evidence compared to CDT.
In some centers with PTE response teams, CDT is used to treat intermediate-risk PTE (often intermediate-high-risk PTE) as coadjuvant therapy to anticoagulation. Still, there is not such a thing as a formal indication for ST. This strategy is based on studies that show that surrogate parameters like right ventricular function improve faster. However, there is no solid evidence regarding improved clinical parameters compared to anticoagulation therapy only.
Added to the indications approved in the European clinical guidelines, at our center, CDT is used in patients with an indication for LT and high risk of bleeding. Evidence shows that 30% to 50% of the patients with an indication for ST won’t receive this therapy afraid that complications will arise (basically severe or intracranial hemorrhages). Factors associated with high risk of bleeding in ST studies are active neoplasms, age ≥ 75 years, low weight (< 50 kg), acute kidney injury (glomerular filtration rate < 30) or active anticoagulation. These patients can benefit from CDT thanks to their lower risk of bleeding—particularly intracranial—based on data of indirect comparisons with ST.
Q.: Please tell us which trials are currently in the pipeline assessing these invasive strategies.
A.: Scientific societies have been developing European multicenter registries like EuroPE-CDT and NCT04037423 and, at national level, the TROMPA registry that is backed by the Interventional Cardiology Association of the Spanish Society of Cardiology.11
Several studies have already been started by device manufactures and are currently in the pipeline. Regarding the MT strategy, the Indigo device is being studied to collect efficacy, safety, and functional recovery data from 600 patients selected in the already started STRIKE-PE registry (NCT04798261). There is also an active registry currently recruiting patients to test the FlowTriever device that will include 1300 participants (FLASH, NCT03761173). Also, the upcoming PEERLESS clinical trial (NCT05111613) will recruit 550 patients with PTE and intermediate-high risk who will be randomized to receive the FlowTriever aspiration system or CDT based on the local routine clinical practice with other devices available in the market. The study primary endpoint will be death, intracranial hemorrhage, major bleeding, clinical impairment or length of stay at an intensive care unit.
The most relevant studies that are being conducted on the EKOS device are the KNOCOUT PE registry (NCT03426124)—in a phase of active recruitment—that will include up to 1500 patients, and the HI-PEITHO trial (NCT04790370). The latter is an international, prospective, multicenter clinical trial that will be comparing anticoagulation vs anticoagulation plus UFLT. The study primary endpoint is a composite of PTE-related mortality, cardiorespiratory decompensation or nonfatal PTE recurrence at 7 days. We should also mention the NCT03581877 trial (Peripheral systemic thrombolysis vs catheter-directed thrombolysis for submassive PE) that is comparing UFLT vs the same dose (24 mg) of rt-PA administered via peripheral vein for 12 hours.
Today’s challenges regarding research are to define procedural success, standardize the endpoints of clinical trials, and establish what intermediate-risk patients with PTE may benefit the most from CDT compared to standard therapy.
FUNDING
None whatsoever.
CONFLICTS OF INTEREST
None reported.
REFERENCES
1. De Gregorio MA, Guirola JA, Kuo WT, et al. Catheter-directed aspiration thrombectomy and low-dose thrombolysis for patients with acute unstable pulmonary embolism: Prospective outcomes from a PE registry. Int J Cardiol. 2019;287:106-110.
2. Salinas, P. Tromboaspiración con sistema FlowTriever en embolia pulmonar aguda. Med Clin (Barc). 2022. https://doi.org/10.1016/j.medcli.2022.02.022.
3. Kuo WT, Banerjee A, Kim PS, et al. Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): Initial Results From a Prospective Multicenter Registry. Chest. 2015;148:667-673.
4. Avgerinos ED, Saadeddin Z, Abou Ali AN, et al. A meta-analysis of outcomes of catheter-directed thrombolysis for high- and intermediate-risk pulmonary embolism. J Vasc Surg Venous Lymphat Disord. 2018;6:530-540.
5. Sista AK, Horowitz JM, Tapson VF, et al. Indigo Aspiration System for Treatment of Pulmonary Embolism. JACC: Cardiovascular Interventions. 2021;14:319-329.
6. Tu T, Toma C, Tapson VF, et al. A Prospective, Single-Arm, Multicenter Trial of Catheter-Directed Mechanical Thrombectomy for Intermediate-Risk Acute Pulmonary Embolism: The FLARE Study. JACC Cardiovasc Interv. 2019;12:859-869.
7. Toma C, Bunte MC, Cho KH, et al. Percutaneous mechanical thrombectomy in a real-world pulmonary embolism population: Interim results of the FLASH registry. Catheterization and Cardiovascular Interventions. 2022;99:1345-1355.
8. Kucher N, Boekstegers P, Müller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129:479-486.
9. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study - PubMed. Available online: https://pubmed.ncbi.nlm.nih.gov/26315743/. Accessed 20 Feb 2022.
10.Avgerinos ED, Jaber W, Lacomis J, et al. Randomized Trial Comparing Standard Versus Ultrasound-Assisted Thrombolysis for Submassive Pulmonary Embolism: The SUNSET sPE Trial. Cardiovascular Interventions. 2021;14(12):1364-1373.
11. Registro TROMPA | SHCI - Sección de Hemodinámica y Cardiología Intervencionista de la SEC (Sociedad Española de Cardiología). Available online: https://www.hemodinamica.com/cientifico/registros-y-trabajos/registros-y-trabajos-actuales/registro-trompa/. Accessed 20 Feb 2022.
QUESTION: In the current management of acute pulmonary thromboembolism (PTE) to what extent is thrombolytic therapy used? and what about invasive therapy?
ANSWER: During the early management of PTE, we’re going after the clinical stabilization of the patient and the alleviation of symptoms, the resolution of vascular obstruction, and the prevention of thrombotic recurrences. The priority of these goals depends on the severity of the patient. Most times (over 90%) these goals can be achieved using conventional anticoagulant treatment to stop the progression of the thrombus while the patient’s endogenous fibrinolytic system resolves the vascular obstruction developing collateral circulation. In a minority of the patients (5% to 10%)—often those with hemodynamic instability (high-risk PTE)—aggressive therapies (of reperfusion) can be used to resuscitate the patient or accelerate the lysis of the blood clot.
When reperfusion therapy is advised for a patient with symptomatic acute PTE, the clinical practice guidelines recommend the use of full-dose systemic fibrinolysis as long as it has not been contraindicated.1 Some of the reasons behind this recommendation are:
- a) Numerous clinical trials (with over 2000 patients included) have assessed the efficacy and safety profile of systemic fibrinolysis (compared to anticoagulation) demonstrating a statistically significant drop of the mortality rate. On the other hand, to this date, only 1 clinical trial has been published assessing the efficacy and safety profile of a catheter-directed treatment (ultrasound enhancement fibrinolysis) in 59 patients with acute PTE and echocardiographic dilatation of the right ventricle.2 The trial used an event of echocardiographic result and was not statistically powered to detect any differences regarding clinical events (mortality, thrombotic recurrences or bleeding).
- b) Percutaneous (local fibrinolysis, embolectomy or a combination of different techniques) and surgical (embolectomy) therapies require infrastructure and experience before they can be applied, and most centers and clinicians who often treat these patients just don’t have what it takes.
Q: Regarding invasive therapy, to what extent is it surgical or percutaneous nowadays?
A: RIETE3 is a real-world, multicenter, and international registry—led by Dr. Manuel Monreal Bosch—of consecutive patients diagnosed with deep venous thrombosis or symptomatic acute PTE. Recent analyses indicate that only 20% of hemodynamically unstable patients with PTE receive reperfusion treatment. Most of these patients (87%) receive systemic fibrinolysis, 10% surgical embolectomy, and 3% percutaneous treatments.
Q: On cardiac catheterization, which is the clinical evidence available regarding intravascular thrombolysis? and regarding thrombus aspiration therapies?
A: The evidence available on the use of percutaneous treatments is still very weak. As I said only 1 clinical trial has been published to this date on the efficacy and safety profile of a catheter-directed therapy (ultrasound enhancement fibrinolysis) in 59 patients with acute PTE and echocardiographic dilatation of the right ventricle (see answer #1).2 Recently, the findings of the prospective FLASH registry have been published including 250 patients treated with percutaneous thrombectomy through the FlowTriever system.4 A total of 3 serious adverse events occurred (1.2%)—all of the severe hemorrhages—that resolved uneventfully. The 30-day all-cause mortality rate was 0.2% (1 death unrelated to PTE). Although the results of clinical registries—that are hypothesis-generating—provide useful medical information, they are no stranger to several biases and confounding factors, which is why they should not be used on a routine basis to assess the efficacy and safety profile of medical procedures. Currently, intermediate-high risk patients are being recruited (sample size, 406-544) with intermediate-high risk PTE for the HI-PEITHO clinical trial. These patients are being randomized to receive conventional anticoagulation or anticoagulation plus ultrasound enhancement local fibrinolysis. The efficacy primary endpoint is assessed by an independent committee 1 week after randomization includes PTE-related death, thrombotic recurrence or hemodynamic collapse.
Q: What are today’s indications for invasive treatment, and how does your center work in this sense? how important is bleeding risk in the decision-making process?
A: At our center we have a PTE code for making decisions on the management of patients with severe PTE (especially high and intermediate-high risk patients). Overall, we follow the recommendations from the Spanish multidisciplinary consensus recently published in Archivos de Bronconeumología.5 We use full-dose systemic fibrinolysis in patients with an indication for reperfusion and without contraindications for use. In patients with an indication for reperfusion and relative contraindications—minor—for full-dose systemic fibrinolysis we use catheter-directed percutaneous treatment (percutaneous thrombectomy, local fibrinolysis or both) or low-dose systemic fibrinolysis. In patients with symptomatic acute PTE, an indication for reperfusion treatment and absolute contraindication for full-dose systemic fibrinolysis we use surgical embolectomy or catheter-directed percutaneous treatment (percutaneous thrombectomy).
From this we can deduce that assessing the bleeding risk is key regarding decision making with reperfusion therapies. In our clinical practice we use the BACS (Bleeding, Age, Cancer, Syncope) scale to identify patients with very low risk of bleeding after the administration of full-dose systemic fibrinolysis.
Q: Can you tell us something on what’s coming in this field, in particular any ongoing studies you think are relevant?
A: As I already mentioned, the HI-PEITHO clinical trial is studying the efficacy and safety profile of ultrasound enhancement local fibrinolysis in intermediate-high risk patients with PTE. Additionally, the PEITHO III clinical trial is currently randomizing intermediate-high risk patients with PTE to receive low-dose systemic fibrinolysis (r-TPA at doses of 0.6 mg/kg up to a maximum of 50 mg) or placebo plus conventional anticoagulation; the efficacy primary endpoint is the same as in the HI-PEITHO trial.
Also, clinical trials are being conducted to assess the efficacy and safety profile of other procedures (non-reperfusion therapies) in patients with severe PTE. In the DiPER clinical trial, a total of 276 patients were recruited to assess the efficacy and safety profile of diuretic therapy to treat PTE with right ventricular dysfunction.6 The administration of a bolus of furosemide improved diuresis and did not make renal function worse. The AIR clinical trial (ClinicalTrials.gov identifier: NCT04003116) is currently studying the efficacy and safety profile of the administration of oxygen to patients with PTE and right ventricular dysfunction.
FUNDING
None whatsoever.
CONFLICTS OF INTEREST
None reported.
REFERENCES
1. Stevens SM, Woller SC, Baumann Kreuziger L, et al. Executive Summary: Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest. 2021;160:2247-2259.
2. Kucher N, Boekstegers P, Muller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129:479-486.
3. Registro informatizado de pacientes con enfermedad tromboembólica en España (RIETE). Disponible en: https://www.riete.org/. Consultado 23 Feb 2022.
4. Toma C, Bunte MC, Cho KH, et al. Percutaneous mechanical thrombectomy in a real-world pulmonary embolism population: Interim results of the FLASH registry. Catheter Cardiovasc Interv. 2022;99:1345-1355.
5. Lobo JL, Alonso S, Arenas J, et al. Multidisciplinary Consensus for the Management of Pulmonary Thromboembolism. Arch Bronconeumol. 2021;58(3):246-254.
6. Lim P, Delmas C, Sanchez O, et al. Diuretic vs. placebo in intermediate-risk acute pulmonary embolism: a randomized clinical trial. Eur Heart J Acute Cardiovasc Care. 2022;11:2-9.
- Debate: Severe bicuspid aortic valve stenosis in non-high-risk surgical patients. In favor of TAVI
- Debate: Severe bicuspid aortic valve stenosis in non-high-risk surgical patients. In favor of surgery
- Debate: Ischemia without obstructive coronary artery disease. An invasive coronary physiological macro- and microvascular assessment is necessary
- Debate: Ischemia without obstructive coronary artery disease. A non-invasive assessment may be sufficient in some cases
Original articles
Review Articles
Original articles
Editorials
Ventricular pressure-volume loop and other heart function metrics can elucidate etiology of failure of TAVI and interventions
aDepartment of Mechanical Engineering, McMaster University, Hamilton, Ontario, Canada
bSchool of Biomedical Engineering, McMaster University, Hamilton, Ontario, Canada
Special articles
Role of computed tomography in transcatheter coronary and structural heart disease interventions
aServicio de Cardiología, Hospital Universitario Álvaro Cunqueiro, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Pontevedra, Spain
bServicio de Cardiología, Hospital de la Santa Creu i Sant Pau, Instituto de Investigación Biomédica Sant Pau (IBB Sant Pau), Barcelona, Spain
cServicio de Cardiología, Complejo Asistencial Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
dCentro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Debate
“Orbiting” around the management of stable angina
The interventional cardiologist’s perspective
aServicio de Cardiología, Complejo Asistencial Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
bCentro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
The clinician’s perspective
aInstituto Cardiovascular, Hospital Clínico San Carlos, Madrid, Spain
bDepartamento de Medicina, Facultad de Medicina, Universidad Complutense, Madrid, Spain