ABSTRACT
Percutaneous coronary intervention of complex coronary artery disease remains challenging and is still associated with suboptimal cardiovascular outcomes. Over the years, different strategies and technologies have been developed to improve these results. Particularly, the development and evolution of intravascular imaging modalities to guide the procedure have improved lesion assessment and preparation, and stent optimization. However, whether these advantages are beneficial in this particular setting is still under discussion. In this article we intend to briefly summarize previous imaging-guided trials and give an outline on the ongoing large trials that are being conducted on imaging-guided interventions in complex coronary disease.
Keywords: Complex percutaneous coronary intervention. Optical coherence tomography. Intravascular ultrasound.
RESUMEN
El intervencionismo coronario complejo es aún un escenario desafiante que todavía se asocia con resultados subóptimos. A lo largo de los años han surgido diferentes estrategias y tecnologías con el objetivo de mejorar dichos resultados. En concreto, el desarrollo y la evolución de herramientas de imagen intravascular para guiar el procedimiento han permitido perfeccionar la evaluación de la lesión y su preparación, y asegurar su optimización. No obstante, los posibles beneficios de su uso en este escenario particular son aún objeto de estudio. En este artículo, el objetivo es resumir brevemente los principales estudios realizados previamente con estas técnicas, así como los ensayos que en la actualidad están en marcha en intervencionismo coronario complejo guiado por imagen.
Palabras clave: Intervencionismo coronario complejo. Tomografía de coherencia óptica. Ecografía intravascular.
Abbreviations IVUS: intravascular ultrasound. OCT: optical coherence tomography. PCI: percutaneous coronary intervention.
INTRODUCTION
Percutaneous coronary interventions (PCI) of complex coronary artery disease namely heavily calcified coronary lesions, bifurcations (including left main coronary artery bifurcations), in-stent restenosis, chronic and acute total coronary occlusions, and long lesions is still associated with suboptimal long-term cardiovascular outcomes. Whether the advances made in stent technology and intracoronary imaging modalities can help reduce this risk is still under discussion. We provide a brief historical overview of intracoronary imaging-guided trials, and large ongoing randomize clinical trials.
After 4 decades of angiography being the mainstay of balloon angioplasty and stent implantation procedures, the evolution of intravascular ultrasound (IVUS), and optical coherence tomography (OCT) on the wake of the availability of new-generation drug-eluting stents and bioresorbable scaffolds has prompted the gradual adoption of both intravascular imaging modalities for PCI guiding purposes. Over the years, several clinical trials and systematic reviews have compared the results and long-term outcomes of angiography vs intracoronary imaging-guided PCI with significant findings.1-12 The latest clinical practice guidelines recommend both imaging modalities to guide stent implantation in a selected subset of patients only (IVUS guidance–Class IIa, and OCT guidance–Class IIb).13,14 This opens new opportunities to set up more contemporary clinical trials in high-risk populations who may benefit the most from these interventions.
Although reports including multicenter trials and systematic reviews have shown the benefits of intravascular imaging-guided PCI compared to angiography-guided PCI, different variations have been observed in the findings reported possibly due to differences in: a) patients and lesion types included in the studies; b) the definition of a specific optimization criteria based on intravascular imaging guidance and differences in those criteria across various studies; c) the length of follow up; and d) the study endpoints. Invariably, the omission or misrepresentation of certain groups of angiographically complex lesions in former studies has triggered the need for trials to focus on this direction.2,3,7,9,15-20
Table 1 shows brief details of former imaging guidance studies and the findings reported.
Table 1. Key former studies on PCI imaging guidance
| Study (N.), NCT | Year | Guidance criteria | Modality | Endpoints | Key findings |
|---|---|---|---|---|---|
| MUSIC (N = 161) NCT N/A | 1998 | Complete stent apposition over its entire length against the vessel wall; MLA: in-stent MLA ≥ 90% of the average reference lumen area or ≥ 100% of the reference segment with the lowest lumen area; in-stent MLA of proximal stent entrance ≥ 90% of the proximal reference lumen area. If in-stent MLA is > 9.0 mm2, in-stent MLA ≥ 80% of the average reference lumen area or ≥ 90% of the reference segment with the lowest lumen area; in-stent MLA of proximal stent entrance ≥ 90% of the proximal reference lumen area; symmetric stent expansion defined by the minimum lumen diameter divided by the maximum lumen diameter ≥ 0.7 | IVUS | Death, MI, coronary artery bypass surgery, and TLR, and clinically and/or angiographically documented (sub)acute thrombotic stent occlusion 30 days after stent implantation | 6-month angiographic outome in IVUS-guided implantation arm, a TLR of 5.7%, and a restenosis rate of 9.7% with the largest MLD 2.12 ± 0.67 |
| AVID (N = 800) NCT N/A | 2000 | MSA should be ≥ 90% of the distal reference vessel lumen cross-sectional area; stent fully apposed; dissections covered by stent | IVUS | The study primary endpoint was the rate of TLR at 12 months determined by the clinical follow-up without having to repeat the angiography | The 12-month follow-up results revealed a TLR rate of 10.1% in the angiography group vs a 4.3% rate in the IVUS group (P = .01; 95%CI, −10.6% to −1.2%) |
| SIPS (N = 269) NCT N/A | 2000 | Complete apposition against the vessel wall of the entire stent; MLA ≥ 90% of the average reference lumen area or ≥ 100% of the lumen area of the reference segment with a MLA > 9.0 mm2; MLA ≥ 80% of the average reference lumen area or ≥ 90% of the reference segment lumen area with the lowest lumen area. Symmetric stent expansion | IVUS | The study primary endpoint was the 6-month angiographic MLD. Secondary endpoints included acute MLD, acute and chronic cost, quality of life, composite clinical event rates, and clinically driven TLR | The clinical follow-up (602 days ± 307 days) showed a significant decrease in clinically driven TLR in the IVUS group compared to the standard guidance group (17% vs 29%, respectively; P = .02) |
| MAIN-COMPARE (N = 975) NCT N/A | 2009 | Specific criteria for IVUS guidance not provided | IVUS | The study primary endpoint was mortality. Secondary endpoints were MI, target vessel revascularization (TVR) or a composite of events | IVUS guidance, especially during drug-eluting stent implantation, may reduce the long-term mortality rate for unprotected left main coronary artery stenosis compared to conventional angiography guidance |
| HOME DES (N = 210) NCT N/A | 2010 | Good apposition; apposition of all stent struts to the vessel wall; Optimal stent expansion (with a MSA = 5 mm2) or a cross-sectional area > 90% of the distal reference lumen cross-sectional area for small vessels/and no edge dissection (5 mm margins proximal and distal to the stent) | IVUS | MACE (death, MI, and reintervention) | No significant differences were reported between the groups at the 18-month follow-up regarding MACE (11% vs 12%; P = NS) |
| CLI-OPCI (N = 670) NCT N/A | 2012 | Stent underexpansion was defined based on established IVUS criteria of optimal stent expansion (eg, in-stent minimal lumen area ≥ 90% of the average reference lumen area or ≥ 100% of the reference segment lumen area with the lowest lumen area) | OCT | Primary endpoint was the 1-year rate of cardiovascular death or MI | The OCT group had a significantly lower 1-year risk of cardiovascular death (1.2% vs 4.5%; P = .010), cardiac death or MI (6.6% vs13.0%; P = .006), and a composite endpoint of cardiac death, MI or new revascularization (9.6% vs 14.8%, P = .044) |
| AVIO (N = 284) NCT N/A | 2013 | Final MSA of, at least, 70% of the hypothetical cross-sectional area of the fully inflated balloon used for post-dilatation. The optimal balloon size for post-dilatation is the average of the media-to-media diameters of the distal and proximal stent segments as well as at the sites of maximum in-stent narrowing. The value is rounded to the lowest 0.00 mm or 0.50 mm. For values ≥ 3.5 mm the operator could downsize the diameter of the balloon based on his best clinical judgment | IVUS | The primary study endpoint was the postoperative lesion minimal lumen diameter. The secondary endpoints were a composite of MACE, TLR, target vessel revascularization, MI, and stent thrombosis at 1, 6, 9, 12, and 24 months | IVUS optimized DES implantation as seen on the complex lesions in the postoperative minimal lumen diameter. No statistically significant differences were found in MACE at the 24-month follow-up. |
| RESET (N = 1574) NCT N/A | 2013 | Specific criteria for IVUS guidance not provided | IVUS | MACE, including cardiovascular death, MI or target vessel revascularization at the 1-year follow-up after DES implantation in short-length lesions | There were no statistically significant differences regarding the MACE outcome between the IVUS-guided and the angiography-guided groups |
| AIR CTO (N = 230) NCT N/A | 2015 | Good apposition, MSA > 80% of the reference vessel area, symmetry index > 70%, and no > type B dissection | IVUS | The primary endpoint was in-stent late lumen loss at the 1-year follow-up | The in-stent late lumen loss in the IVUS-guided group was significantly lower compared to the angiography-guided group at the 1-year follow-up (0.28 mm ± 0.48 mm vs 0.46 mm ± 0.68 mm; P = .025) with a significant difference of the “in-true-lumen” stent restenosis between the 2 groups (3.9% vs13.7%; P = .021) |
| CTO IVUS (N = 402) NCT01563952 | 2015 | a) MSA ≥ distal reference lumen area; b) stent area at CTO segment ≥ 5 mm2 vessel area permitting; and c) complete stent apposition | IVUS | The primary endpoint was the occurrence of cardiovascular death. The secondary endpoint was MACE defined as a composite of cardiovascular death, MI or target vessel revascularization at 12 months | The IVUS-guided CTO intervention did not reduce cardiovascular mortality significantly. The occurrence of MACE was significantly lower in the IVUS-guided group compared to the angiography-guided group (2.6% vs 7.1%) |
| IVUS-XPL (N = 1400) NCT01308281 | 2016 | MLA greater than the lumen cross-sectional area at the distal reference segments post-PCI | IVUS | The primary outcome measure was a composite of MACE, including cardiovascular death, target vessel MI or ischemia-driven TLR at the 1-year follow-up analyzed by intention-to-treat | IVUS-guided stent implantation was associated with a significant 2.9% absolute reduction, and a 48% relative reduction in the risk of MACE at the 1-year follow-up compared to angiography-guided stent implantation |
| ILUMIEN III (N = 450) NCT02471586 | 2016 | MSA: achievement of, at least, acceptable stent expansion (a minimum stent area of, at least, 90% in both the proximal and distal halves of the stent relative to the closest reference segment) Acceptable stent expansion: the MSA of the proximal segment is ≥ 90% and < 95% of the proximal reference lumen area, and the MSA of the distal segment is ≥ 90% and < 95% of the distal reference lumen area | IVUS, OCT | The primary efficacy endpoint was the post-PCI minimum stent area as seen on the OCT at a masked independent core laboratory after completing recruitment in all randomly allocated participants with primary outcome data available. The primary safety endpoint was procedural MACE | OCT guidance was non-inferior to IVUS guidance (one-sided 97.5% lower confidence interval, −0.70 mm²; P = ·001), but not superior either to IVUS-guidance (P = .42) and angiography guidance (P = .12). There were no significant differences in the MACE outcome |
| OPINION (N = 800) NCT01873222 | 2016 | In-stent MLA ≥ 90% of the average reference lumen area; complete stent apposition over its entire length against the vessel wall; symmetric stent expansion defined by minimum lumen diameter/maximum lumen diameter ≥ 0.7; no plaque protrusion, thrombus or edge dissection with potential to provoke flow disturbances | IVUS, OCT | The primary endpoint was TVF defined as a composite of cardiovascular death, target vessel MI, and ischemia-driven target vessel revascularization 12 months after the PCI | TVF occurred in 21 (5.2%) out of the 401 patients undergoing OFDI-guided PCI, and in 19 (4.9%) out of the 390 patients undergoing IVUS-guided PCI, which proved the non-inferiority of OFDI-guided PCI with respect to the IVUS-guided PCI (hazard ratio, 1.07; upper limit of one-sided 95%CI, 1.80; P value for non-inferiority = .042) |
| ULTIMATE (N = 1448) NCT02215915 | 2021 | a) In-stent MLA > 5.0 mm or 90% of the MLA at the distal reference segments; b) plaque burden 5 mm proximal or distal to the stent edge is < 50%; and c) no edge dissection involves the media with a length > 3 mm | IVUS | The primary endpoint was the risk of TVF at the 3-year follow-up | IVUS-guided DES implantation was associated with significantly lower rates of TVF and stent thrombosis at the 3-year follow-up among all-comers |
95%CI, 95% confidence interval; CTO, chronic total coronary occlusion; DES, drug-eluting stent; IVUS, intravascular ultrasound; MACE, major adverse cardiovascular events; MLA, minimum lumen area; MI, myocardial infarction; MLD, minimum lumen diameter; MSA, minimum stent area; NA, not available; NS, not significant; OFDI, optical frequency domain imaging; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; TLR, target lesion revascularization; TVF, target vessel failure. | |||||
Subsequently, new ongoing studies are assessing the effect of PCI imaging guidance on the clinical outcomes over longer follow-up periods and the value of guiding interventions with imaging modalities when treating specific lesion subsets like in-stent restenosis, calcified lesions, and long lesions. Table 2 highlights the ongoing PCI guidance trials.
Table 2. Ongoing studies on PCI imaging guidance
| Study, NCT | Modality | Study design | Study objective | Imaging criteria | Clinical endpoints |
|---|---|---|---|---|---|
| IMPROVE, NCT04221815 | IVUS vs angiography | Prospective multileft, international, single-blind clinical investigation No. of subjects: approximately 2500-3100 randomized subjects Follow-up period: 2 years | To demonstrate the superiority of an IVUS-guided stent implantation strategy compared to an angiography-guided stent implantation strategy achieving larger post-PCI lumen dimensions, and improving the clinical cardiovascular outcomes of patients with complex angiographic lesions | Optimal stent deployment is considered to have been achieved if the following 3 criteria are met on the final IVUS: MSA > 90% of the distal reference lumen area. No edge dissection involving the media with an arc ≥ 60° and length ≥ 3 mm Absence of geographic miss defined as plaque burden > 50% within 5 mm from the proximal or distal stent edge or both | Target vessel failure outcomes at 12 months defined as a composite of cardiovascular death, target vessel MI or clinically indicated target vessel revascularization |
| IVUS-CHIP, NCT04854070 | IVUS vs angiography | Randomized, controlled, multileft, international, event-driven, post-marketing study. A total of 2020 patients will be randomized in a 1:1 fashion to the IVUS-guided PCI vs the angio-guided PCI | To demonstrate the superiority of IVUS guidance compared to angio guidance regarding target vessel failure | Final MSA > 5 mm2 or MSA < 90% of distal reference lumen Plaque burden < 50% within 5 mm from the proximal or distal stent edge No edge dissection involving the media and > 3 mm in length | Target vessel failure defined as a composite of cardiovascular death, target vessel MI or clinically indicated target vessel revascularization |
| OPTIMAL, NCT04111770 | IVUS vs angiography | Randomized, controlled, multileft, international study | To demonstrate the superiority of IVUS- vs angiography-guided stent implantation in patients with LMCA disease, and also improving the clinical outcomes | MSA > 5 (LCX), > 6 (LAD), > 7 (bifurcation point), > 8 (LMCA) Malapposition < 0.4 mm Absence of edge dissection defined as ≥ 60° and ≥ 2 mm in length Plaque burden at the edge of the stent < 50% | Patient-oriented composite endpoint (POCE): a composite of all-cause death, any strokes, any MIs, any clinically indicated revascularizations at the 2-year follow-up |
| ILUMIEN IV, NCT03507777 | OCT vs angiography | Prospective, multileft, randomized, controlled clinical trial No. of subjects: between 2490 and 3656 Follow-up period: 2 years Expected study duration: approximately 2 years | To demonstrate the superiority of OCT- vs angiography-guided stent implantation in the patients’ clinical outcomes | To achieve: Acceptable stent expansion (an MSA of, at least, 90% in both the proximal and distal segments of the stent relative to the closest reference segment). Both proximal/distal reference segments have a minimal lumen area ≥ 4.5 mm2 Absence of a major edge dissection defined as ≥ 60° of the vessel circumference at the dissection site and ≥ 3 mm in length | Target vessel failure, a composite of cardiovascular death, target vessel MI or ischemia-driven target vessel revascularization |
| DKCRUSH VIII, NCT03770650 | IVUS vs angiography | Randomized, controlled, multicenter trial Sample size: 556 patients Allocation 1:1 | To assess superiority of IVUS-guided vs angiography-guided DK Crush stenting in complex bifurcations | For LMCA: MSA ≥ 10mm2 (LM), 7mm2(LAD), 6mm2 (CX) Stent expansion index ≥ 90% (of distal reference lumen area in LCX) Symmetry index > 0.8 For non-LMCA: MSA ≥ 6mm2 in the main vessel, and ≥ 5mm2 in the ostial side branch Stent expansion ≥ 90% of distal reference lumen area Symmetry index > 0.8 | The primary outcome is the rate of 12-month target vessel failure: Cardiac death, target vessel myocardial infarction, clinically driven target vessel revascularization |
| OCTOBER, NCT03171311 | OCT vs angiography | Randomized, investigator-initiated, multileft trial. The calculated sample size is 1200 patients in total allocated in a 1:1 fashion | To show the superiority of OCT-guided stent implantation compared to standard angiographic-guided implantation in bifurcation lesions | Adequate vessel and stent expansion (> 90%) Full stent apposition Optimal lesion coverage | The primary outcome measure is a 2-year composite endpoint of cardiovascular death, target lesion myocardial infarction, and ischemia-driven target lesion revascularization |
| OCTIVUS, NCT03394079 | OCT vs IVUS guided PCI | Multicenter, randomized, controlled trial. “All-comer” population ample size:2000 patients Allocation 1:1 | To compare the clinical efficacy and safety of OCT-guided and IVUS-guided PCI | Optimization criteria by IVUS or OCT: Stent expansion > 80% by average reference lumen area Absence of large dissections (> 60º, > 2mm length, flap extending to media or adventicia). Absence of malapposition Avoidance of a landing zone in a plaque burden < 50% or lipid-rich tissue at stent edge Distal lumen reference based (0.25mm up-round) or EEM reference based (0.25mm down-round) | The primary outcome is target vessel failure: cardiac death, target vessel myocardial infarction or ischemia-driven target vessel revascularization at 1 year. |
IVUS, intravascular ultrasound; LAD, left anterior descendent coronary artery; LCX, left circumflex artery, LMCA, left main coronary artery; MI, myocardial infarction; MSA, minimum stent area; OCT, optical coherence tomography; PCI, percutaneous coronary intervention. | |||||
ONGOING CLINICAL TRIALS ON INTRAVASCULAR ULTRASOUND GUIDANCE
The IMPROVE (Impact on revascularization outcomes of IVUS-guided treatment of complex lesions and economic impact, NCT04221815) trial,17 a multicenter, prospective, single-blind 3100 patient study, aims to demonstrate the superiority of IVUS-guided stent implantation over the angiography-guided stent implantation strategy in complex lesions (including chronic total coronary occlusions, calcified lesions, long lesions, bifurcations, and in-stent restenosis) based on the different post-PCI minimum stent area, and target vessel failure outcomes reported at 12 months defined as a composite endpoint of cardiovascular death, target vessel myocardial infarction, and ischemia-driven target vessel revascularization (table 2 and figure 1).
Figure 1. Main patient and lesion characteristics included in these ongoing large intracoronary imaging trials. * Functional inclusion criteria: functional significance of the main vessel lesion or documented ischemia of the main vessel territory or other objective documentation of lesion significance. Objective evidence of ischemia is required for all target lesions except for those with > 80% diameter stenosis that may be considered significant. PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; NSTEMI, non—ST-segment elevation myocardial infarction; SB, side branch.
The IVUS-CHIP trial (Intravascular ultrasound guidance for complex high-risk indicated procedures, NCT04854070) is a randomized, controlled, multicenter, international, event-driven, post-marketing study. A total of 2020 participants with complex coronary lesions (angiographic heavy calcifications, ostial lesions, true bifurcation lesions, left main coronary artery lesions, chronic total coronary occlusions, in-stent restenosis, long-lesions) or requiring elective mechanical circulatory support assisted PCI will be randomized in a 1:1 fashion to receive IVUS-guided PCI vs angio-guided PCI. The study aims to demonstrate the superiority of the IVUS guidance strategy in terms of the primary endpoint, target vessel failure, defined as a composite endpoint of cardiovascular death, target vessel myocardial infarction or clinically indicated target vessel revascularization (table 2 and figure 1).
The OPTIMAL (Optimization of left main PCI with intravascular ultrasound, NCT04111770) study is a randomized, controlled, multicenter, international study. A total of 800 patients will be randomized in a 1:1 fashion to receive IVUS-guided PCI vs qualitative angiography-guided PCI. Patients with a de novo left main coronary artery lesion (ostial, shaft or distal) eligible for a PCI according to the heart team will be included. All left main coronary artery bifurcations according to the Medina classification 100, 110, 101, 011, 010, 111, 001 (and LMCA equivalent) can be included. Patients with a previous coronary artery bypass graft and no patent bypass on the left main coronary artery can be included too. The study primary endpoint is a patient-oriented composite endpoint: a composite of all-cause mortality, any strokes, any myocardial infarctions, and any clinically indicated revascularizations at the 2-year follow-up (table 2 and figure 1).
The DK CRUSH VIII trial (NCT03770650)19 is a randomized, controlled, multicenter study that aims to assess the superiority of IVUS-guided versus angiography-guided DK crush stenting in 556 patients with complex bifurcation lesions based on DEFINITION criteria. Its primary endpoint is the rate of cardiac death, target vessel failure, target vessel myocardial infarction or target vessel revascularization at 12 months (table 2 and figure 1).
ONGOING CLINICAL TRIALS ON OPTICAL COHERENCE TOMOGRAPHY
In the past, the ILUMIEN III study (NCT02471586), that reported on the non-inferiority of OCT compared to IVUS (minimal stent area; one-sided 97.5% lower confidence interval, –0.70 mm²; P = .001) proved the superiority of the OCT-guided stent implantation strategy compared to the angiography-guided stent implantation strategy achieving larger post-PCI lumen dimensions, and improving clinical cardiovascular outcomes in patients with high-risk clinical characteristics and/or high-risk angiographic lesions. The ILUMIEN IV (NCT03507777) trial that has completed recruitment (3600 patients initially planned) intends to demonstrate the superiority of an OCT-guided stent implantation strategy over an angiography-guided stent implantation strategy achieving larger post-PCI lumen dimensions, and improving clinical cardiovascular outcomes in patients with high-risk clinical characteristics like diabetes and/or high-risk angiographic lesions. The result of both studies and their similar endpoints will be shedding light on the role played by intravascular imaging guidance especially for the management of complex coronary lesions (table 2 and figure 1).
Another OCT clinical trial is the European trial on optical coherence tomography optimized bifurcation event reduction (OCTOBER, NCT03171311), a randomized, investigator-initiated, multicenter trial aimed at showing the superiority of OCT-guided stent implantation compared to standard angiographic-guided implantation in bifurcation lesions. Stratified randomization: a) left main or non-left main coronary artery disease, and b) upfront planned 1-stent technique with kissing balloon inflation or a 2-stent technique.18
A direct comparison of OCT and IVUS is planned in the OCTIVUS trial (NCT03394079), a multicenter, controlled trial of an all comers population that will be randomized to either OCT-guided PCI or IVUS-guided PCI.20 The primary endpoint is death, target vessel myocardial infarction and ischemia-driven target vessel revascularization at one year (table 2 and figure 1).
CONCLUSIONS
Undoubtedly, intravascular imaging plays a role optimizing stent implantation, the extent of which remains to be fully grasped particularly in complex populations and lesion subsets. Based on previous reports that showed overwhelming evidence in favor of intravascular imaging-guided PCI, it is expected that these large 4 contemporary randomized clinical trials will show a reduction of major adverse cardiovascular events and, therefore, favor the use of intracoronary imaging in these populations and lesion subsets. One may also predict a significant increase in the use of IVUS/OCT based on the positive results, increased reimbursements, and hopefully a change in the societal guideline recommendations.
FUNDING
None whatsoever.
AUTHORS’ CONTRIBUTIONS
H.M. Garcia-Garcia is responsible for the study design and draft of the manuscript. E. Fernández-Peregrina, K.O. Kuku, and R. Diletti also drafted the manuscript and gave their critical review.
CONFLICTS OF INTEREST
H.M. Garcia-Garcia, and K.O. Kuku declared having received Institutional grant support from Biotronik, Boston Scientific, Medtronic, Abbott Vascular, Neovasc, Shockwave, Phillips, and Corflow. R. Diletti also declared having received institutional grant support from Biotronik, and Boston Scientific. E. Fernández-Peregrina declared having received a research grant from Sociedad Española de Cardiología.
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* Corresponding author: Division of Interventional Cardiology, MedStar Washington Hospital Center, 100 Irving St., NW Washington DC 20010, United States.
E-mail addresses: hector.m.garciagarcia@medstar.net; hect2701@gmail.com (H.M. Garcia-Garcia).
ABSTRACT
Ischemic heart disease is the most common cause of death worldwide. In patients with ST-segment elevation myocardial infarction (STEMI), optimizing primary percutaneous coronary intervention is crucial to improve prognosis. Over the years, many studies have been published on the value of second-generation stents, strategies to reduce myocardial damage, how to achieve complete revascularization and also on percutaneous mechanical circulatory support devices, which all are attractive therapeutic options to treat patients with STEMI complicated by cardiogenic shock. In this review we will be discussing how primary percutaneous coronary intervention can be optimized with respect to stent selection and revascularization strategy to reduce myocardial damage and improve clinical outcomes. In addition, we review published data on the use of mechanical circulatory support devices in patients with STEMI complicated by cardiogenic shock.
Keywords: ST-segment elevation myocardial infarction. Percutaneous coronary intervention. Drug-eluting stent. Cardiogenic shock.
RESUMEN
La cardiopatía isquémica es la causa más común de mortalidad en todo el mundo. En pacientes con infarto agudo de miocardio con elevación del segmento ST (IAMCEST), la optimización de la intervención coronaria percutánea primaria es crucial para mejorar el pronóstico. Durante estos últimos años, se han publicado muchos estudios sobre el valor de los stents de segunda generación, sobre estrategias para reducir el daño miocárdico, sobre cómo conseguir la revascularización completa y finalmente también sobre dispositivos de apoyo circulatorio mecánico percutáneo que representan una opción terapéutica atractiva en pacientes con infarto agudo de miocardio con elevación del segmento ST (IAMCEST) complicado con shock cardiogénico. En esta revisión discutimos cómo se puede optimizar la intervención coronaria percutánea primaria con respecto a la selección de stents y estrategia de revascularización, con el fin de reducir el daño miocárdico y mejorar los resultados clínicos. Además, revisamos los datos publicados sobre el uso de dispositivos de apoyo circulatorio mecánico en pacientes con IAMCEST complicado por shock cardiogénico.
Palabras clave: Infarto de miocardio con elevación del segmento ST. Intervención coronaria percutánea. Stent farmacoactivo. Shock cardiogénico.
Abbreviations CS: cardiogenic shock. DES: drug-eluting stents. IABP: intra-aortic balloon pump. LV: left ventricle. MVD: multivessel coronary artery disease. PCI: percutaneous coronary intervention. STEMI: ST-segment elevation myocardial infarction. VA-ECMO: venoarterial extracorporeal membrane oxygenation.
INTRODUCTION
Ischemic heart disease is the leading cause of death across the world. Over the last few decades, thanks to the improvements made in reperfusion and antithrombotic therapies, and primary prevention, the relative rates of ST-segment elevation myocardial infarction (STEMI) and long-term and acute mortality have decreased significantly.1 However, despite this reduction, the mortality rate of patients with STEMI is still substantial with in-hospital mortality rates ranging from 4% to 12%, and a 1-year follow-up mortality rate close to 10%.2-4
In STEMI patients, mortality depends on various factors like the Killip classification at presentation, old age, the presence of cardiovascular risk factors, left ventricular function, the spread of the disease in the coronary arteries, and the delayed administration of reperfusion therapy. An early diagnosis and restoration of myocardial blood flow from symptom onset are essential to optimize myocardial salvage and lower the mortality rate.5 Primary percutaneous coronary intervention (PCI) is the reperfusion strategy of choice in STEMI patients if timely performed.5 Optimizing the primary reperfusion strategy is essential to reduce myocardial damage and prevent further reperfusion lesions.
The objective of this review is to give a general overview on current and future percutaneous devices that can potentially improve the benefit of primary PCI including stents, revascularization strategies, and mechanical circulatory support devices for the management of STEMI complicated with cardiogenic shock (CS) like the intra-aortic balloon pump (IABP), the Impella device (Abiomed, Danvers, Massachusetts, United States), TandemHeart (Pittsburgh, Pensilvania, United States), and venoarterial extracorporeal membrane oxygenation (VA-ECMO).
THROMBUS ASPIRATION
Intracoronary thrombus can be found in most STEMI patients. Distal embolization has been reported in 5% to 10% of the cases and can cause obstruction what worsens the results.6 Some time ago, the thrombectomy technique was proposed as a coadjuvant therapy to help restore the coronary blood flow at epicardial level by reducing the chances of distal embolization, the no-reflow phenomenon, and the size of the infarction. Also, it could reduce the thrombotic load prior to stent implantation, thus reducing the rate of associated complications due to stent malapposition. Manual thrombus aspiration was systematically recommended in primary PCI following small randomized clinical trials and a meta-analysis that showed reperfusion improvement with lower cardiovascular mortality rates.7-9 However, after the publication of 2 large statistically powered randomized clinical trials to detect the superiority of routine manual aspiration vs PCI, only 1 change in the recommendation has occurred.5 Neither the TOTAL (N = 10 732 patients) nor the TASTE (N = 7244 patients) clinical trials showed any differences with the thrombectomy in the clinical outcomes compared to the PCI alone.10,11 Also, the TOTAL trial posed a safety issue associated with a higher risk of stroke in patients treated with thrombectomy compared to those treated with PCI alone.12
Based on these data, thrombus aspiration is now not recommended as a routine strategy in STEMI patients treated with a PCI primary PCI. However, it can be considered in patients with high thrombotic load after vessel recanalization. A subanalysis of the EXAMINATION trial (N = 1498) confirmed that the use of thrombectomy was associated with a higher rate of direct stenting, a lower rate of postdilatation, and a smaller number of stents implanted with a larger stent size.13 However, the optimized angiographic result did not impact the long-term outcomes since no differences were seen in the clinical endpoints reported between the arms at the 2-year follow-up.
SELECTING THE TYPE OF STENT
Coronary stent implantation is the recommended therapy during a primary PCI for the management of STEMI patients. Direct stenting without predilatation in STEMI culprit lesions can reduce the embolization of the plaque components, the rate of no-reflow phenomenon, and increase myocardial perfusion.14 This hypothesis was confirmed in the post-hoc analysis of the HORIZONS-AMI trial and the EUROTRANSFER registry; both showed a lower mortality rate at the 1-year follow-up associated with the use of direct stenting.15,16
Delayed stent implantation after restoring coronary flow has also been proposed through a minimalistic mechanical procedure to reduce the risk of no-reflow phenomenon.17 Several observational trials showed benefits in terms of an improved left ventricular ejection fraction and a lower rate of adverse events with the delayed compared to the immediate stent implantation strategy in STEMI patients.18,19 Also, a proof-of-concept randomized clinical trial (DEFER-STEMI, N = 411) reported a lower no-reflow phenomenon rate with the delayed stent implantation strategy in a population of patients with STEMI.20 However, the DANAMI 3-DEFER trial randomized 1215 STEMI patients to receive delayed vs immediate stent implantation. At the 2-year follow-up no differences were seen in the primary endpoint of all-cause mortality, hospital admission due to heart failure, recurrent infarction, and any unplanned revascularizations between the study groups (18% vs 17%; hazard ratio [HR], 0.99; 95% confidence interval [95%CI], 0.76–1.29; P = .92).21 Afterwards, the MIMI randomized clinical trial (N = 140), that excluded patients with a high thrombotic load, and the INNOVATION trial (N = 114) did not show any changes either in the infarction size or microvascular obstruction with the delayed compared to the immediate stent implantation strategy.22,23 Finally, a meta-analysis of randomized and observational clinical trials found no improvement either in the rates of no-reflow, death, myocardial infarction or repeat revascularizations with the delayed stent implantation strategy for the management of STEMI.24 Surprisingly, an improved left ventricular (LV) function was reported in the long-term. For all these reasons, to this date, the delayed stent implantation strategy is ill-advised in the primary PCI.
Another aspect to be taken into consideration before performing a primary PCI is what device should be implanted. Several randomized clinical trials and meta-analyses assessing first-generation drug-eluting stents (DES), whether sirolimus or paclitaxel, showed lower in-stent restenosis and target lesion revascularization rates compared to conventional bare metal stents (BMS).25-32 However, safety concerns soon appeared given the high rate of late thrombosis associated with first-generation DES.33-35
To overcome this problem, second-generation DES with different drugs, thinner struts, and durable or bioresorbable polymers more biocompatible have been designed. The COMFORTABLE AMI clinical trial randomized 1161 STEMI patients on a 1:1 ratio to receive a BMS or a biodegradable polymer biolimus-eluting stent. At the 1-year follow-up a lower rate of major adverse cardiovascular events was reported in the biolimus-eluting group compared to the BMS group (4.3% vs 8.7%; HR, 0.49; 95%CI, 0.30–0.80; P = .044) mainly triggered by a lower risk of spontaneous myocardial infarction and target lesion revascularization.36 Similarly, at the 2-year follow-up a lower rate of major adverse cardiovascular events was reported in the biolimus-elutin group (5.8% vs 11.9%; HR, 0.48; 95%CI, 0.31–0.72]; P < .001).37 Both at the 1- and 2-year follow-ups, the rates of definitive or probable stent thrombosis were also numerically lower with the DES although not statistically significant.36,37
The EXAMINATION clinical trial38,39 randomized 1498 STEMI patients to receive a second-generation everolimus-eluting stent (EES) or a BMS. At the 1-year follow-up, the EES was superior to the BMS with a significantly lower rate of definitive thrombosis, and definitive or probable thrombosis (0.5% vs 1.9%, and 0.9% vs 2.5%, respectively; P = .019 for both]).38 Also, at the 5-year follow-up, the rate of all-cause mortality was significantly lower in the EES group compared to the BMS group (9% vs 12%; HR, 0.72; 95%CI, 0.52–0.10]; P = .047)39. Also, a meta-analysis of both the EXAMINATION and the CONFORTABLE-AMI clinical trials found a significant reduction of the risk of definitive thrombosis with the use of the DES (HR, 0.35; 95%CI, 0.16–0.75; P = .006) compared to the BMS.40 Given the conclusions of these clinical trials, the DES is currently the device of choice according to the recommendations established in the clinical practice guidelines published by the European Society of Cardiology on the management of STEMI.5
The researchers of the EXAMINATION trial investigators have recently reported that the 10-year follow-up results confirm the superiority of EES over BMS in terms of patient or device related cardiovascular adverse events. Between the 5- and the 10-year follow-up periods, a low rate of adverse cardiovascular events was associated with failed devices.41
Fully bioresorbable vascular scaffolds (BVS) were introduced to overcome the long-term limitation of the permanent presence of metal within the coronary artery. The data on their use for the management of STEMI is still limited. Although unavailable for clinical use, we believe the existing data should be discussed. The early experiences with the Absorb BVS (Abbott Vascular, Illinois, United States) for the management of STEMI showed positive and negative clinical results alike.42-44 The TROFI II clinical trial randomized 191 STEMI patients to receive a BVS or a EES and found no differences between the 2 regarding scarring of the infarct-related artery.45 However, other studies showed disturbing data following the high rate of thrombosis with the BVS device. In the BVS EXAMINATION clinical trial, the safety and efficacy profile of BVS vs EES was compared in STEMI patients. At the 1- and 2-year follow-up periods, no differences were found in the device-oriented composite endpoint between both groups.46,47 We should mention that at the 2-year follow-up, the rate of definitive thrombosis was often higher in the BVS group compared to the EES group (3.3% vs 1.0%; P = .081). At the 5-year follow-up, the risk of the device-oriented composite endpoint was higher in the BVS group, indicative that the chances of obtaining favorable outcomes at a very long-term follow-up is low.48
The BVS STEMI STRATEGY-IT clinical trial was designed to reduce the rate of adverse events. It proved that a prespecified BVS implantation strategy in STEMI patients treated with a primary PCI was feasible and yielded good clinical outcomes at the 30-day and 1-year follow-up periods (rate of device thrombosis between 0.2 and 0.4%, respectively).49,50
We should mention that the long-term results of randomized clinical trials that proved a significantly higher rate of BVS thrombosis were the reason of their withdrawal from the market.51-53
The Magmaris (Biotronik, Bülach, Switzerland) is a magnesium-based bioresorbable sirolimus-eluting stent. It has shown promising early results at the 1-year follow-up in stable patients with very limited data on STEMI.54 The MAGSTEMI trial is the only randomized clinical trial that compared the efficacy and safety profile of the Magmaris device in STEMI patients.55 This study randomized 150 patients to receive a primary PCI with Magmaris vs sirolimus-eluting stents using a prespecified implantation technique. Compared to the sirolimus-eluting stent, the Magmaris device showed a greater capacity of vasomotor response to drug agents (whether independent from the endothelium or endothelium-dependent) at the 1-year follow-up. However, the Magmaris device was associated with a lower angiographic efficacy and a higher rate of clinical restenosis, but no thrombotic issues.56 In the prespecified MAGSTEMI-optical coherence tomography substudy, both the Magmaris and the sirolimus-eluting stent showed a low degree of neointimal healing. However, lumen dimensions were smaller with the Magmaris at the 1-year follow-up. Although Magmaris advanced bioresorption state complicates the assessment of the scaffold, this seems to be the main mechanism of restenosis.57,58 Cases of significant delayed resorption of the Magmaris device have been reported, and intraluminal scaffold remnants have been found 2 years after implantation.59
MULTIVESSEL CORONARY ARTERY DISEASE
Around 50% of STEMI patients show multivessel coronary artery disease (MVD).60 Multiple clinical trials have studied the best revascularization strategy: treat the culprit lesion only vs complete revascularization. The PRAMI trial randomized 465 patients with STEMI and MVD to culprit lesion treatment only or revascularization of all obstructive lesions (angiographic stenosis > 50%) during the index procedure. Complete revascularization during the index procedure was associated with a 65% lower relative risk in the primary endpoint (cardiac death, infarction or refractory angina) compared to treating the culprit lesion only.61 Similarly, the CvLPRIT trial (N = 269) showed that complete revascularization (angiographic stenosis > 70%) during the index hospitalization was superior to the PCI of the infarct-related lesion only in the composite endpoint of death, reinfarction, heart failure, and repeat revascularization at the 12-month follow-up.62
Measuring the fractional flow reserve of coronary flow to guide the need for non-culprit lesion revascularization has been proposed. The DANAMI-3-PRIMULTI trial (N = 627) proved that fractional flow reserve-guided complete revascularization significantly reduced the risk of future cardiovascular adverse events compared to any other invasive procedure after the primary PCI. This effect is due to a significantly lower number of repeat revascularization procedures because the rates of all-cause mortality and non-fatal reinfarction did not vary between the groups.63 Also, the Compare-Acute trial (N = 885) proved that fractional flow reserve-guided complete revascularization during the index procedure significantly reduced the rate of cardiovascular adverse events.64
The COMPLETE clinical trial included 4041 patients randomized to complete revascularization vs culprit lesion therapy who were followed for up to 3 years. Complete revascularization was superior to the PCI only in the culprit lesion to reduce the risk of cardiovascular death or myocardial infarction, and the risk of cardiovascular death, myocardial infarction or ischemia-induced revascularization.65 Currently, the BioVasc trial (NCT03621501) is studying how to optimize the treatment algorithm for patients with acute coronary syndrome with MVD to find out what the best time is to perform complete revascularization, whether immediate or delayed.66
According to the current guidelines of the European Society of Cardiology, during hospitalization and before hospital discharge, the complete revascularization of the non-culprit lesions of patients with STEMI and MVD should be considered.5 However, this indication is likely to change after the publication of the upcoming COMPLETE trial clinical results.
In the specific case of CS-complicated STEMI patients, the CULPRIT-SHOCK trial randomized 1075 patients with CS-complicated STEMI with MVD to be treated with a PCI on the infarct-related artery or a multivessel PCI of all lesions (angiographic stenosis > 70%). Both at the 30-day and 1-year follow-up, the PCI performed on the culprit lesion only significantly reduced the risk of death or renal replacement therapy.67,68 This difference was mainly triggered by a significantly lower mortality rate. In this sense, the European Society of Cardiology published an update of its guidelines on the management of STEMI where, in the presence of STEMI with CS and MVD only the culprit lesion of the acute event should be treated.69
CARDIOGENIC SHOCK
Around 5% to 8% of STEMI patients also show CS, which is defined as persistent hypotension (systolic pressure < 90 mmHg) with signs of peripheral hypoperfusion. CS is one of the leading causes of death with in-hospital mortality rates that can be over 50%.70 In patients with CS refractory to drug therapy, percutaneous mechanical circulatory support can help reduce the LV workload and oxygen demand, keep organs and coronary arteries perfused, and stand as a bridging therapy to a more definitive therapy.71,72 Currently, we have assist devices from the LV to the aorta (IABP and Impella), from the left atrium to systemic arterial circulation (TandemHeart), and from the right atrium to systemic arterial circulation (VA-ECMO). The technical characteristics of percutaneous mechanical circulatory support systems currently available are shown on table 1.
Table 1. Technical characteristics of percutaneous mechanical circulatory support devices currently available
| BIAC | Impella | TandemHeart | ECMO-VA | |
|---|---|---|---|---|
| Hemodynamic effect | Unloading of LV pressure and volume | Unloading of LV pressure and volume | Unloading of LV volume | Unloading of RV and LV pressure and volume |
| Mechanism | Aorta | LV to the aorta | LA to the aorta | RA to the aorta |
| Heart blood flow | 0.3 L/min to 0.5 L/min | 1 L/min to 5 L/min | 2.5 L/min to 5 L/min | 3.0 L/min to 7.0 L/min |
| Peripheral resistances | ↓ | ↓ | ↑ | ↑↑↑ |
| Size | 8 Fr | 13-Fr to 22-Fr | 21-Fr inflow cannula and 15-Fr to 17-Fr outflow cannula | 18-Fr to 21-Fr inflow cannula and 15-Fr to 22-Fr outflow cannula |
| Implantation complexity | Low | - Moderate with Impella 2.5 | High | High |
| Recommended use duration | Weeks | 7 days | 14 days | 7 days |
| Contraindications | - Severe aortic regurgitation | - Severe aortic valvular heart disease | - Severe peripheral vascular disease | - Moderate-to-severe aortic regurgitation |
| Complications* | - Thrombocytopenia | - Hemolysis | - Migration of the cannula | - Circuit thrombosis |
* Complications that are common to all devices: bleeding and infections associated or not with puncture site, vascular complication, and neurological damage. Fr, French sizing; IABP, intra-aortic balloon pump; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; VA-ECMO, venoarterial extracorporeal membrane oxygenation. | ||||
Left ventricular assist device to the aorta
Intra-aortic balloon pump
Intra-aortic balloon pump (IABP) has been the most commonly used mechanical support device until 2010. After this year, its use dropped significantly after some clinical trial results questioned its efficacy.73 It requires an 8-Fr introducer sheath into the femoral or axillary arteries and consists of a balloon mounted over a catheter that is placed in the descending aorta. The balloon is inflated during diastole and deflated during systole. The IABP increases the diastolic aortic pressure, reduces the aortic systolic pressure, increases the mean systemic arterial pressure, reduces the LV volume and diastolic pressure, and increases the coronary perfusion pressure. However, the hemodynamic support provided by the IABP is strictly associated with the LV function since it is less effective when it shows severe dysfunction.
Observational trials and meta-analyses have traditionally supported the use of IABP in CS-complicated STEMI.74-76 However, prospective clinical trials have showed no benefit whatsoever from the IABP therapy in patients with STEMI with or without CS. The CRISP AMI trial (N = 337) showed that IABP implantation right before the PCI to treat an anterior STEMI without CS did not reduce the size of the infarction or improve the short-term survival rate.77 The TACTICS trial randomized 57 patients with acute myocardial infarction and 48 hours of fibrinolytic therapy to receive the IABP or optimal medical therapy. This trial found no differences in the mortality endpoint at the 6-month follow-up.78 Also, the IABP SHOCK trial6 randomized 45 patients with STEMI and CS for IABP implantation or standard medical therapy and found no significant hemodynamic improvements after additional therapy with the IABP.79
The IABP SHOCK II trial randomized 600 patients with STEMI and CS not associated with mechanical complications to compare IABP implantation the optimal medical therapy.80 It was expected that all patients underwent early revascularization (predominantly with PCI) and received the optimal medical attention available. At the 30-day follow-up, no differences were seen in the all-cause mortality rate between the IABP and the optimal medical therapy (39.7% vs 41.3%; relative risk, 0.96; 95%CI, 0.79-1.17]; P = .69) or in the length of the stay in the intensive care unit, renal function, major bleeding, peripheral ischemic complications, sepsis or stroke.80 At the 12-month follow-up, no differences were seen either in the mortality rate and secondary endpoints reported.81 A meta-analysis of 12 randomized clinical trials and 15 observational studies found no benefits from the IABP therapy in the management of STEMI or in the 30-day mortality rate regardless of the presence (odds ratio [OR], 0.94; 95%CI, 0.69–1.28) or absence (OR, 0.98; 95%CI, 0.57–1.69) of CS. Currently, based on the available evidence, the European Society of Cardiology clinical practice guidelines always contraindicate the IABP in patients with CS.5
The Impella system
The Impella system is a continuous axial flow pump that is inserted into the LV in a retrograde fashion through the aortic valve and provides active support by expelling suctioned blood from the LV into the ascending aorta, thus restoring blood flow to ischemic organs.82 The Impella device increases the mean arterial pressure, reduces the LV pressure and volume, and increases coronary flow. It comes in 3 different sizes: 2.5 (maximum output, 2.5 L/min), 3.7 (Impella CP, maximum output, 3.7 L/min), and 5.0 (maximum output, 5 L/min). The smallest devices can be placed percutaneously through a 12-Fr to 14-Fr introducer sheath and the 5.0 device through a 22-Fr introducer sheath.82
Two large registries confirmed the safety of the Impella 2.5 system in high-risk complex PCIs.83,84 The ISAR-SHOCK trial randomized 26 patients with STEMI and CS to receive the Impella 2.5 system or the IABP. The endpoint, a change in the cardiac index from baseline to 30 min after implantation, improved significantly in the Impella group. However, secondary endpoints like lactic acidosis, hemolysis, and mortality at the 30-day follow-up did not vary between the 2 arms.85 At the 30-day follow-up, the cohort overall mortality rate was 46%. The IMPRESS in Severe Shock clinical trial randomized 48 patients with mechanical ventilation associated with CS after STEMI to receive the Impella system or IABP implantation. We should mention that the device was implanted at the discretion of the treating physician. The trial proved that, compared to the IABP, the Impella system did not reduce the 30-day mortality rate, and the overall mortality rate at the 6-month follow-up was 50%.86 Both vascular complications and major bleeding were more common in the Impella group.
We should mention that, to date, the Impella device has not been compared to standard therapy in patients with CS in a proper statistically powered randomized clinical trial regarding relevant clinical events. In this sense, the DanGer Shock clinical trial (NCT01633502) will include 360 patients with STEMI and CS who will be randomized to receive circulatory support with the Impella system or standard medical therapy.87 The study is still recruiting patients and its primary endpoint is all-cause mortality at the 6-month follow-up.
Back in 2018 a groundbreaking idea was introduced: the use of the Impella system to unload the LV and, therefore, reduce the size of myocardial infarction in animal models with STEMI but without CS.88 These animal models led to the design and conduction of the DTU-STEMI pilot study that randomized 50 STEMI patients without CS to LV unloading with the Impella CP device or optimal medical therapy. This trial revealed that LV unloading therapy prior to STEMI reperfusion with the Impella device was feasible and not associated with a significant delay in STEMI reperfusion.89 However, the use of the unloading therapy was not associated with a reduced infarction size at 1-month follow-up. Currently recruiting patients, the DTU-STEMI clinical trial (NCT03947619) will be enrolling 668 patients to test the hypothesis of the use of the LV unloading therapy with the Impella CP device to reduce the infarction size as seen on the cardiovascular magnetic resonance imaging.
Left atrium-to-systemic circulation assist devices
TandemHeart
The TandemHeart is an extracorporeal ventricular assist device to aspirate oxygenated blood from the left atrium and pump it into the lower abdominal aorta or iliac arteries to avoid running through the LV. The 21-Fr inflow cannula is inserted via femoral vein access and advanced through the interatrial septum towards the left atrium. The 15-Fr to 17-Fr outflow arterial cannula and the system can provide up to 5 L/min of blood flow.90 The device basically reduces the LV preload and left atrial volume by removing blood from the left atrium, thus reducing the LV stress and workload. It also increases the systemic mean arterial pressure and myocardial perfusion.
There is little experience regarding registries and studies on this device. Thiele et al.91 informed on the use of this device in 18 patients with STEMI and SC. The device provided up to 4 L/min of assisted cardiac output. Patients improved their cardiac index and mean arterial pressure, and reduced their pulmonary artery pressure, pulmonary capillary wedge pressure, and central venous pressure with an average 4 days on ventilatory assistance. Kar et al.92 published a series of 117 patients with CS treated with the TandemHeart device that quickly reversed the end-stage hemodynamic compromise seen in patients with STEMI and CS refractory to the IABP and vasopressor support. A randomized clinical trial included 42 patients treated with the IABP (N = 14) or the TandemHeart device (N = 19). The TandemHeart device improved the patients’ hemodynamic parameters significantly even in IABP-refractory patients. However, the mortality rate was similar in both groups.93 To this date, we do not know of any other randomized clinical trials on this technology.
Right atrium-to-systemic arterial circulation assist devices
Extracorporeal membrane oxygenation
VA-ECMO is a cardiopulmonary support system that aspirates blood from the femoral vein or internal jugular vein through a 21-Fr cannula. Through an artificial membrane lung, carbon dioxide is eliminated and oxygen is added to venous blood to later return to the arterial system through a 15-Fr to 22-Fr outflow cannula via the femoral or axillary arteries.93 One of the greatest advantages of ECMO is that it can be implemented everywhere (emergency room, cath lab, etc.) since it is fully portable and does not require fluoroscopic or echocardiographic guidance for a successful implantation. This device provides circulatory support of up to 7 L/min in patients with circulatory and respiratory failure. Some of its limitations are that the VA-ECMO system cannot unload the LV, which can trigger an increased afterload, which is in turn associated with LV distension, worsening of LV function, LV thrombus, and swelling or untreatable alveolar hemorrhage.94 For these reasons it has been proposed that ECMO should be administered with other devices like the IABP and the Impella to reduce pulmonary artery pressures and the dimensions of the LV.95,96 A multicenter, international cohort study included 686 consecutive patients with CS (not due to STEMI exclusively) treated with ECMO. Those patients who underwent LV unloading with the Impella device had a better prognosis and a lower mortality rate, but also higher rates of implantation related bleeding and vascular complications.97 Other authors also recommend procedures like percutaneous balloon atrial septostomy, to allow left-to-right shunting, or the administration of dobutamine to improve contractility and reduce the afterload.94
Aortic regurgitation, aortic dissection, severe peripheral arterial disease, and some ethical considerations are absolute contraindications to ECMO implantation.90 Active bleeding is a relative contraindication because ECMO requires heparin for anticoagulation; however, it has been used in some high-risk patients without heparin since it was the only strategy to save the patient’s life.98 Complications are mainly vascular like lower limb ischemia, compartmental syndrome, major bleeding, stroke, air embolism, and serious infection.90
Yet despite ECMO is widely used in experienced centers, the data supporting its use in patients with acute myocardial infarction complicated with CS are mostly single-center small case-series. Sheu et al. conducted a single-center retrospective observational registry that compared the clinical outcomes of patients with STEMI treated with a primary PCI. The investigators studied 2 different timeframes:1993-2002 for the non-ECMO cohort and 2002-2009 for the ECMO cohort. The study proved that the ECMO assisted PCI improved results at the 30-day follow-up.99 However, interpreting these results is difficult because of the significant discrepancies seen in the treatment strategies used between the groups. In a different study, Muller et al. included 138 STEMI patients treated with ECMO. They developed a mortality risk score in the intensive care unit setting called the ENCOURAGE score. The variables associated with worse prognosis were age > 60 years, female sex, body mass index > 25, Glasgow score < 6, elevated creatinine and lactate serum levels, and prothrombin times < 50%. Survival rates at 6-month and 1-year follow-up were 41% and 38%, respectively.100
Currently, the effects of the use of VA-ECMO on the mortality of patients CS-complicated STEMI is being studied in 3 randomized clinical trials: the EUROSHOCK (NCT03813134), the ANCHOR (NCT04184635), and the ECLS-SHOCK (NCT03637205) clinical trials.101 On top of studying mortality, these clinical trials are an opportunity to analyze the indication, way, and effect of LV unloading.102
CONCLUSION
Despite the improvements made in reperfusion therapies, the mortality of STEMI patients is still high. Together with drug therapy, the rapid restoration of coronary flow and stent implantation are the strategies recommended (figure 1). The routine use of manual thrombus aspiration is discouraged given the lack of clinical benefit compared to the PCI alone. Regarding the type of device selected, second-generation DES are the standard of choice in STEMI patients treated with a primary PCI since the short and long term results are better compared to BMS and first generation DES. In patients with STEMI and MVD, the current evidence recommends complete revascularization, although the optimal time to perform it remains unknown. Exclusively in the case of patients with CS, only the revascularization of the infarct-related artery is advised. Patients with CS-complicated STEMI is undoubtedly the clinical setting with less significant advances. Their mortality rate is still somewhere around 40% to 50%. To this date, several clinical trials are being conducted to assess the impact of circulatory assist devices like the Impella and VA-ECMO on these patients’ mortality rate.
Figure 1. Current evidence and future perspectives of percutaneous coronary interventions for the management of ST-segment elevation myocardial infarction. The green + sign indicates that the procedure is recommended by the European Society of Cardiology clinical practice guidelines; the red minus sign (−) indicates that the procedure is not recommended; the yellow question mark (?) symbol indicates that there is not enough evidence (for or against) to recommend it. ECMO, extracorporeal membrane oxygenation; STEMI, ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention.
FUNDING
None.
AUTHORS’ CONTRIBUTION
L. Ortega-Paz wrote the review draft on the current state of the interventional management of myocardial infarction. S. Brugaletta, and M. Sabaté conducted the critical review of the manuscript with the corresponding changes of content and format.
CONFLICTS OF INTEREST
M. Sabaté is a consultor for Abbott Vascular, and IVascular with no links to this study whatsoever. S. Brugaletta is a consultor for Boston Scientific, and IVascular with no links to this study. L. Ortega-Paz declared no conflicts of interest whatsoever.
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* Corresponding author: Unidad de Cardiología Intervencionista, Departamento de Cardiología, Instituto Cardiovascular, IDIBAPS, CardioCV, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain.
E-mail address: masabate@clinic.cat (M. Sabaté).
ABSTRACT
Brief review of current indications, materials, techniques, complications, results, and controversies around percutaneous procedures for the management of pulmonary valve and arterial branches disease. This article gives the interventional cardiologist a perspective on the material currently available.
Keywords: Valvuloplasty. Angioplasty. Percutaneous valve.
RESUMEN
Se presentan las indicaciones actuales, el material, las técnicas, las complicaciones, los resultados y las controversias de los procedimientos percutáneos que permiten abordar la patología valvular y de las ramas pulmonares. El presente artículo ofrece una perspectiva del material actualmente disponible de forma clara para el cardiólogo intervencionista.
Palabras clave: Valvuloplastia. Angioplastia. Valvulas percutaneas.
Abbreviations CHD: congenital heart disease. CPC: cavopulmonary connection. PB: pulmonary branches. PR: pulmonary regurgitation. PS: pulmonary stenosis. PVA: pulmonary valve atresia. RV: right ventricle. RVOT: right ventricular outflow tract.
PULMONARY VALVE STENOSIS
The origin of pulmonary valve stenosis (PVS) is almost exclusively congenital. It amounts to 7% to 10% of all congenital heart diseases (CHD). Although it is often an isolated defect, it can be associated with other congenital malformations.
Acquired stenosis is extremely rare and is associated with carcinoid syndrome or rheumatic fever. An emergent form is the stenosis of surgical bioprosthesis or valved conduits.
PVS can coexist with infundibular or supravalvular pulmonary stenosis, the latter often associated with Noonan, Williams or Alagille syndromes as well as with congenital rubella.
Clinical presentation is varied and goes from critical stenosis or pulmonary valve atresia (PVA) in the newborn baby to mild stenosis that can go untreated.
Although its presentation in the adult life is often asymptomatic, in cases of severe stenosis, exertional dyspnea, ventricular dysfunction, arrhythmias or sudden death have been reported. In this group, it can have a native presentation after previous surgery or valvuloplasty.
Etiology
PVS can have 3 anatomopathological presentations1 (figure 1):
– Typical PVS. It is the most common: a typical tricommissural valve with mild thickening of the leaflets and commissural fusion. The valve annulus is normally developed, and post-stenotic dilatation often occurs. Valve opening is typically dome-shaped with a central stenotic orifice. It rarely presents calcification.
– PVS due to dysplastic valve. It represents almost 20% of all cases pf PVS, although it is common of Noonan syndrome. Valve leaflets are thickened and myxomatous with limited opening and scarce commissural fusion. It can be associated with annular hypoplasia and even with proximal pulmonary trunk.
– PVS associated with other CHD such as interatrial communication, interventricular communication, transposition of great arteries, double outlet right ventricle (RV) o tetralogy of Fallot. The valve is often bicuspid or even unicuspid. It can be associated with infundibular or pulmonary supraventricular stenosis and annular hypoplasis.
Figure 1. A: Valve stenosis due to dysplastic valve (left). B: Typical valve stenosis.
Pulmonary valvuloplasty
Since 1982, percutaneous pulmonary valvuloplasty has been the technique of choice to treat pulmonary valve stenosis in newborn babies until adult life. The goal here is to overextend and tear the leaflets at commissural raphe level.
This technique is often curative and has a low rate of restenosis at the follow-up. It can often be treated with a second procedure.
The degree of immediate residual pulmonary regurgitation (PR) does not usually go from severe to mild; instead, it can progress with the passing of time. Despite of this, the need for valve replacement is not usually the case.
Indications
The natural history of pulmonary valve stenosis is associated with the degree of obstruction. Although the Doppler-derived mean pressure gradient is most reliably associated with the peak-to-peak hemodynamic gradient, the international guidelines2-3 establish the degree of obstruction based on the instantaneous Doppler-derived peak pressure gradient:
– Mild stenosis (instantaneous Doppler-derived peak pressure gradient < 36 mmHg or peak velocity < 3 m/sec). The course of the disease is often benign and it can be compatible with living a normal life. In the adult patient, evaluations every 5 years are advised.
– Moderate stenosis (instantaneous Doppler-derived peak pressure gradient of 36 mmHg to 64 mmHg or peak velocity of 3-4 m/sec). Although often asymptomatic, the limited RV cardiac output can give rise to the appearance of exertional dyspnea or fatigue; 20% of cases can progress towards a greater degree of obstruction. Evaluations every 2 years are advised.
– Severe stenosis (instantaneous Doppler-derived peak pressure gradient > 64 mmHg, peak velocity > 4 m/sec or Doppler mean gradient > 40 mmHg. It is associated with the presence of symptoms, RV dysfunction or cyanosis. Treatment is always indicated here.
The indications for the management of pulmonary valve stenosis are shown on table 1.4,5
Table 1. Treatment indications in pulmonary valve stenosis
| Critical stenosis of the newborn baby |
| Severe pulmonary valve stenosis (Doppler-derived peak pressure gradient > 60 mmHg or Doppler-derived mean pressure gradient > 40 mmHg) in asymptomatic patient |
| Moderate pulmonary valve stenosis (instantaneous Doppler-derived peak pressure gradient > 50 mmHg or Doppler-derived mean pressure gradient > 30 mmHg) in symptomatic patient |
| Surgery will be indicated in association with: |
| Moderate or severe pulmonary regurgitation. |
| Subvalvular or supravalvular stenosis. |
| Severe tricuspid regurgitation. |
| Symptomatic dilatation of pulmonary artery due to extrinsic compression of nearby structures. |
| Need for surgical correction of other associated anomalies or arrhythmia surgery (the Maze technique). |
| Percutaneous valvuloplasty can be the first option in case of dysplastic valves compared to surgery. Still, the rate of success can be lower. |
Technique and material
The percutaneous pulmonary valvuloplasty technique has been reported extensively1 and it can be performed under conscious sedation, local anesthesia or even general anesthesia in the pediatric patient. A total of 100 IU/Kg of sodium heparin are administered up to a maximum of 5000 IU. Transthoracic or transesophageal echocardiography are not often used here.
Femoral vein access is the most common of all, although other alternative accesses can also be used such as the jugular vein or the transhepatic access. In cases of large pulmonary valve annulus, 2 simultaneous venous accesses may be necessary to perform the double balloon technique. Arterial access is optional.
After the baseline registry of pressures, a right ventriculography will be performed preferably in the lateral and posterolateral projections with a 30º cranial inclination. The measurements of the pulmonary annulus are taken during systole at valve-leaflet junction level.
After crossing the pulmonary valve with a catheter, the exchange guidewire will be in position to provide the distal pulmonary artery with high support (preferably the inferior lobar artery). Different types of balloon catheter can be used and early diameters 1.2-1.25 times larger compared to the pulmonary annulus diameter are advised (figure 2A). If the hemodynamic gradient remains > 30 mm Hg and in the absence of significant PR, it is recommended to repeat the procedure with a new balloon catheter until reaching a 1.4 ratio. The 1.5 ratio should be respected except for cases of dysplastic valves. The recommended length of the balloon is 20 mm in newborns and infants, 30 mm in pediatric patients, and 40 mm in adults.
Figure 2. A: Balloon pulmonary valvuloplasty. B: Double balloon pulmonary valvuloplasty.
In case of large valve annulus, the double balloon technique can be used (figure 2B); in this case, both balloons should have the same length. The effective diameter of the combined 2 balloon catheters6 is shown on table 2, and can be estimated as follows:
Table 2. Effective diameter using the double balloon technique
| Diameter | 6 mm | 7 mm | 8 mm | 10 mm | 12 mm | 14 mm | 15 mm | 16 mm | 18 mm | 20 mm | 22 mm | 24 mm |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 6 mm | 9.0 | |||||||||||
| 7 mm | 10.7 | 11.5 | ||||||||||
| 8 mm | 11.5 | 12.3 | 13.1 | |||||||||
| 10 mm | 13.3 | 14.0 | 14.8 | 16.4 | ||||||||
| 12 mm | 15.1 | 15.8 | 16.5 | 18.0 | 19.6 | |||||||
| 14 mm | 16.9 | 17.6 | 18.3 | 19.7 | 21.3 | 22.9 | ||||||
| 15 mm | 17.8 | 18.5 | 19.2 | 20.6 | 22.1 | 23.7 | 24.5 | |||||
| 16 mm | 18.7 | 19.4 | 20.1 | 21.5 | 23.0 | 24.6 | 25.4 | 26.2 | ||||
| 18 mm | 20.6 | 21.2 | 21.9 | 23.3 | 24.7 | 26.3 | 27.0 | 27.8 | 29.5 | |||
| 20 mm | 22.5 | 23.1 | 23.7 | 25.1 | 26.5 | 28.0 | 28.8 | 29.5 | 31.1 | 32.7 | ||
| 22 mm | 24.4 | 25.0 | 25.6 | 26.9 | 28.3 | 29.7 | 30.5 | 31.2 | 32.8 | 34.4 | 36.0 | |
| 24 mm | 26.3 | 26.9 | 27.5 | 28.8 | 30.1 | 31.5 | 32.2 | 33.0 | 34.5 | 36.1 | 37.7 | 39.3 |
Effective diameter = 0.82 (diameter 1 + diameter 2)
No significant differences have been reported in terms of effectiveness between the percutaneous pulmonary valvuloplasty with single or double balloon.
Results and follow-up
The rate of immediate procedural success is close to 90% with a very low mortality rate (0.24%) and scarce major complications (0.35%). In the dysplastic pulmonary valve, the rate of success is even lower.1 Surgery can be spared as a second option in this type of valvular anatomy.
The rate of restenosis seen at the follow-up is 21% in the historic series and between 8% and 10% in the most recent clinical trials.7-9 Risk factors are the presence of dysplastic valve, residual hemodynamic gradient ≥ 30 mmHg, and use of a balloon-to-annulus ratio < 1.2.
In the absence of severe-to-mild PR, repeating the percutaneous valvuloplasty is the selection of choice except for the management of valve dysplasia where surgery can be indicated.
At the follow-up, PR was present in 40% to 90% of the patients with an increase seen at the follow-up. Risk factors are a higher degree of early stenosis, younger age at the moment of the valvuloplasty, and a greater balloon-to-annulus ratio.
Despite this, valve replacement is rarely indicated with indications that will be based on the presence of symptoms like ventricular volumes and RV function parameters is rare. Studies suggest that the same indication parameters as in the corrected TOF with residual PR could be used.10
Special situations
Pulmonary valve atresia
PVA is a complex CHD characterized by the complete obstruction of pulmonary flow and observed within the first days of life following the ductus arteriosus physiological closure; it is incompatible with life if left to its natural progression.
The basic anatomical marker is valve atresia, often membranous, with fused leaflets and valve annulus hypodevelopment. Other lesions are often associated with this main anomaly, among them, the variable RV and tricuspid valve hypodevelopment and coronary circulation anomalies. Both the pulmonary trunk and arteries often appear normal.
The management of these patients includes early stabilization by keeping the temporal maintenance of ductal patency with prostaglandin E1 infusion. The ultimate therapeutic approach will depend on the severity of the associated lesions. The early opening of the valve is indicated in patients with the most favorable prognosis in terms of sufficiently developed RV and tricuspid valve and lack of RV-dependent coronary circulation.
This technique is often performed via percutaneous access11,12 (videos 1-8 of the supplementary data) by accessing the RV and the right ventricular outflow tract (RVOT) or mammary artery via venous access and inserting a right coronary curved (JR) catheter under the imperforate valve plane. Once its correct position has been secured it is advanced through a system of microcatheter and radiofrequency guidewire, with which the valve plane is pierced. Afterwards, a sequential valvuloplasty with balloon catheter will be performed.
Although after this procedure, antegrade flow is established from the RV, this flow is rarely enough to keep an adequate level of arterial oxygen saturation due to different factors: persistent RVOT obstruction at valvular/infundibular level, restrictive behavior of the RV, and tricuspid valve hypodevelopment. All of it conditions an insufficient pulmonary flow through the natural pathway and a significant right-to-left interatrial shunt with the corresponding desaturation. For this reason, an accessory source of pulmonary flow is often required that should remain beyond the neonatal period.
Over the last few years, a new alternative has been implanting a coronary stent into the ductus arteriosus. This can be performed during the same procedure or during a second procedure via venous antegrade or arterial retrograde access. The goal here is to implant a 3 mm to 4 mm coronary stent in such a way that ductal length is fully covered, thus avoiding stent protrusion into the aortic or pulmonary borders.
This technique facilitates keeping enough pulmonary flow and arterial oxygen saturation until the RV is properly developed. Ductal stent usually closes spontaneously by endoluminal proliferation within the first year of life. In some cases, a new in-stent stent implantation may be required at the follow-up.
Fetal pulmonary valvuloplasty
Fetal pulmonary valvuloplasty is a rare technique applicable to fetuses with prenatal diagnosis of critical pulmonary valve stenosis or PVA and risk of progression towards RV hypoplasia. It is often performed between the 21st and 28th weeks of pregnancy. The goal here is to promote a better intrauterine development of right heart structures, thus favoring biventricular physiology after birth.
Through simultaneous ultrasound guidance and after achieving a proper fetal position, a transuterine, fetal transthoracic, and cardiac puncture is performed by accessing the RVOT with a 22-G Chiva needle. The pulmonary valve is then punctured with the needle in case of atresia and a 0.014 inch coronary guidewire is distally placed. Mounted over this guidewire and inside the needle, a very low-profile coronary balloon catheter is advanced and valve dilatation is performed.
Regarding results, this is a complex technique that requires multidisciplinary experience and collaboration. One of the difficulties is achieving the right needle orientation since the size of the RV cavity is so small and its geometry so complex. There is a high rate of complications including fetal arrhythmias, pericardial effusion or even fetal death.
A recent international multicenter clinical trial13 documented this procedure in 58 fetuses and reported a 55% rate of complications including 7 deaths. Compared to the disease progression of patients treated with a similar cohort of treatment-naive fetuses, a greater tendency towards biventricular physiology was confirmed after birth in the first group (87% vs 43%). Despite this, to this date, no criteria have been established with indications for this technique. Therefore risks, the group experience, and the possible benefits should all be assessed in each particular case.
PERCUTANEOUS PULMONARY VALVES
Many CHD require RVOT reconstruction using a patch, a bioprosthesis or a conduit between the RV and the pulmonary artery. In the tetralogy of Fallot, 90% of the patients who undergo surgery during childhood will reach the adult age and a significant number of them will develop regurgitation or PS following the annulus section or use of conduits. When and how to treat these conditions is still controversial since there is no expert consensus, and the American, Canadian, and European guidelines5 establish general rules with suboptimal levels of evidence. Also, each particular case shows characteristics unforeseen by the algorithms proposed.
Surgeons use different materials to solve these dysfunctions: allografts, porcine pericardium based heart valves—with and without support—, mechanical valves, and valved (hand-made) and non-valved conduits. Over the last 2 decades, percutaneous coronary interventions have broken into our setting pushed by the development of bioprosthesis mounted on stents; still, we don’t know when to treat asymptomatic patients: precocity in replacement is associated with faster deterioration and more procedures being performed—each one with its own risk—while late procedures may no longer stop or revert the deterioration of ventricular function and volumes.
The morphology of a dysfunctional RVOT is very complex, determines the therapeutic approach (the “pyramid” morphology is not very compatible with self-expanding valves), and behaves dynamically. Echocardiography is not enough here. Instead, the computed tomography scan is required to see the coronary anatomy. Also, the cardiac magnetic resonance imaging (that cannot be performed in all cases due to problems with clips, pacemakers or heart valves causing interferences) facilitates the assessment of volumes and function, and the visualization of such dynamic behavior. Currently, the RV function is more important than the RV size both to indicate the implant and to make follow-up assessments. The coronary anatomy does not always show the behavior during and after implantation. As a matter of fact, the different RVOT measure changes during implantation don’t cause linear changes in coronary arteries, which is why coronary angiography still plays an essential role. The length of self-expanding valves is significantly greater compared to balloon-expandable (and surgical) valves, which is why the total distance in the area left for implantation becomes crucial. We have known for years that the pulmonary and the aortic valves don’t share the same architecture and work differently. Also, that the same heart valves operate differently in the aortic and pulmonary positions (actually, they may even not close effectively).14
Indications and historical perspective
The indications for percutaneous pulmonary valves included in the European5 and American15 guidelines are similar to surgical replacement. In symptomatic patients the indication is well established. Asymptomatic patients, instead, require ECG data (absolute prolonged QRS interval duration > 180 or progression), hemodynamic data (like a correlation of pressures between the RV and the left ventricle > 0.7), and Doppler-derived peak and mean pressure gradients > 50 and > 30, respectively. But, above all, magnetic resonance imaging data in cases of significant pulmonary regurgitation (regurgitation fraction > 30%): right ventricular end-diastolic volumes > 160 mL/m2, double right end-diastolic volume compared to the left one, end-diastolic volume > 80 mL/m2, and RV ejection fraction < 0.40-0.45 (or negative progression).
The first heart valve ever implanted percutaneously was the Bonhoeffer pulmonary valve back in 2000. It was based on the idea of suturing a bovine jugular vein with the valve in a vascular stent. The valve was given the name Melody (Medtronic Inc, United States) and obtained the CE marking and the Canadian marking in 2006 and the United States Food and Drug Administration marking back in 2010. It is indicated for elderly patients with dysfunctional surgical conduits. Its off-label use has increased and it is used in patients of up to 20 kg of weight and in native RVOTs,16 with technical modifications (previous stent implantation in the implant area) to minimize some of the most common complications reported (stent fracture), but with precautions due to the significant numbers of infectious endocarditis reported (a problem shared with the surgical bovine heart valve Contegra (Medtronic, United States). The limitation of valve sizes available (18 mm, 20 mm, and 22 mm) is also a problem because many patients with regurgitation have large-caliber pulmonary trunks, which has led to imaginative solutions for extended uses.
In 2008 The Edwards SAPIEN heart valve (Edwards Lifesciences LLC, United States) for aortic positioning started being used in the right position thanks to the COMPASSION clinical trial that proved it safe and effective for conduits with moderate or severe pulmonary regurgitation with or without stenosis.17 Its sizes are larger (23, mm 26 mm, and 29 mm), it does not fracture, and the incidence rate of infectious endocarditis is lower (although, on this regard, the literature available is not that “solid”). In 2016 the Edwards SAPIEN XT heart valve was approved by the European and American regulatory agencies for use in children and adults with regurgitation or PS; the current SAPIEN 3 heart valve is approved for the aortic position only, but numerous off-label implants have been reported in the pulmonary position.
The procedure requires a meticulous prior preparation. An arterial access and 2 venous accesses, preferably femoral, are required. It can also be implanted via jugular vein access. The angiographic study (figure 3) serves 2 purposes: a) study the anatomy and sizes of the “trunk” or conduit and pulmonary branches (PB) for which different projections are needed (the RV outflow tract is better seen on the right anterior oblique projection at 20º + cranial at 20º and in the lateral position; still, changes need to be made in this particular case), and inject contrast agents both in the trunk and in the RV while the trunk is occluded with a balloon catheter; and b) study the anatomical relations of proximity since the adjacent structures can be compressed (the ascending aorta or the coronary arteries). To that end, while the balloon catheter remains inflated in the pulmonary artery, an aortogram or coronary angiography or both is performed. A 34 mm or 35 mm very compliant cutting balloon for interatrial communication can be used. However, at times, the balloon compliance exceeds the target diameter of the implant causing coronary or aortic compression. When this happens, other balloons of identical diameter to the target implant will be required. In the presence of a calcified conduit, the approach should be gradual given the risk of rupture. If the Melody valve is used, a previous stent should always be implanted—covered if the conduit is calcified—which is not required in the remaining heart valves.
Figure 3. Angiography examples. A: in pulmonary trunk, individualized, in right anterior oblique projection at 20º + cranial at 40º. B: with balloon catheter for interatrial communication measurement and morphologic assessment, in the same projection. C: in lateral projection showing how over-dilatation occludes the left anterior descending coronary artery that originates from the right coronary artery. D: selective coronary angiography with a balloon of the same diameter as the implantable valve diameter, without coronary obstruction, the same projection as in A. E: with the same balloon as in D, in lateral projection.
There is no consensus as to whether the entire procedure should be performed in 1 or 2 stages leaving the first stage to anatomical/physiological study and stent implantation.
Pulmonary prosthetic valves available
There are 2 large groups of heart valves available, balloon-expandable valves and self-expanding valves. The former have been around a little longer, are approved by regulatory agencies, over 10 000 of them have already been implanted worldwide, have greater radial strength, allow a better control of the diameter to reach, shorten when dilated, and are extremely demanding from the technical point of view. Self-expanding valves are more modern, are in the pipeline in several clinical trials still pending approval, reach larger diameters, and are longer; still, there can be problems in the pulmonary trunk distal portion as they don’t shorten, there is no control over their diameter (they reach their nominal value), and no re-dilatations are possible. Figure 4 shows the heart valves currently available for pulmonary use.
Figure 4. Percutaneous pulmonary valves. A: Melody valve (Medtronic, United States). B: Edwards XT valve (Edwards Lifesciences LLC, United States). C: Venus valve (Venus MedTech, China). D: Harmony valve (Medtronic, United States). E: Pulsta valve (Taewoong Medical, South Korea).
The Melody TPV valve
The Melody TPV valve (Medtronic Inc, United States)18 is a balloon-expandable valve. It is built from a bovine jugular vein with an 18 mm native valve sutured to a platinum-iridium CP stent (NuMED, Canada). The overall length of the entire system is 28 mm and shortens in relation to the final diameter. It can expand from 16 mm to 22 mm in diameter (it probably also works up to 24 mm). Valve crimping is manual and it is delivered and released using Medtronic Ensemble patented system—a version of the double balloon angioplasty BIB (NuMED Inc., United States)—with a 22-Fr profile in its distal portion and a 16-Fr profile in its proximal portion, of 100 mm in length; it is advanced through a high-support guidewire allocated in a pulmonary branch (preferably the left one).
The Edwards SAPIEN valve
The Edwards SAPIEN valve (Edwards Lifesciences LLC, United States)18 is a balloon-expandable valve with porcine pericardium leaflets mounted on a cobalt chromium stent. Its height is smaller compared to the Melody valve. The SAPIEN XT THV model has been approved for the pulmonary position and is built in 23 mm (height of 14.3 mm), 26 mm (height of 17.2 mm), and 29 mm (height of 19.1 mm). Valve crimping is performed with a specific device, proximal to the position of the balloon, “mounted” on it, and once in the inferior vena cava, delivered and released using Novaflex patented system (Edwards Lifesciences, United States) with 18-Fr, 19-Fr or 20-Fr profiles depending on the valve diameter. It is very rigid and not easy to advance or retrieve especially with a previous stent already implanted, which can end up damaging the tricuspid valve. The SAPIEN 3 THV model is built of the same diameters (in heights of 18 mm, 20 mm, and 22.5 mm) but it is an evolution whose internal covered portion is fairly shorter (9.3 mm, 10.2 mm and 11.6 mm). It has an outer protection of polyethylene terephthalate to minimize the possibility of leaks. Its stent has different geometries in the proximal and distal portions so that it shortens even more in its proximal border. It is delivered through the “deflectable” Edwards Commander Delivery System of 14-Fr for the 23 mm and 26 mm valves, and 16-Fr for the 29 mm valve with a patented introducer sheath (Edwards eSheath). It has been reported that through greater volume inflations compared to the nominal volume, the SAPIEN 3 valve can reach 30 mm.
The Venus P-valve
The Venus P-valve (Venus MedTech, China) is designed for native tracts. It is a self-expanding, trileaflet valve of porcine pericardium with a 30 mm in length nitinol stent covered by porcine pericardium—except for its distal portion—that dilates in both borders (1 cm in each border), with radiopaque marks to facilitate it location; the diameter of the valve is that of the nondilated portion (18 mm to 34 mm). Delivery system is MedTech patented with a 20-to-22-Fr distal caliber, a 16-Fr proximal caliber, and a 22-to-24-Fr introducer sheath. Valve crimping is manual by submerging it in a cold saline solution.19
Two clinical trials have been conducted to achieve the CE marking, one in China and the other one in Europe. Both have been completed and are in the data evaluation stage with inclusion criteria similar to those of the remaining valves.
The Harmony mTPV 25 valve
The Harmony mTPV 25 valve (Medtronic, United States) is a self-expanding nitinol structure with a polyester covering and a porcine pericardium valve stitched in the middle. Its conceptual design is vast: the first clinical trials started in the United States in 2013, but, to this date, the valve is still under constant modification (Harmony TPV 22, Harmony TPV 25, and modified Harmony TPV 25). It is available for research purposes only.
The PULSTA valve
The PULSTA valve20 (Taewoong Medical, South Korea) is designed for native tracts. It is a nitinol, trileaflet, self-expanding valve of porcine pericardium also covered with porcine pericardium except for its proximal and distal (major) portions. It has radiopaque marks to outline the area covered. Numbering corresponds to the narrowest area— commissure level—from 18 mm to 32 mm. A larger diameter (1 mm to 2 mm) compared to the pulmonary trunk is selected; the dome-shaped area measures 4 mm more compared to the narrow area. It is built in 2 different lengths: 33 mm and 38 mm. The delivery system caliber is 18-Fr for up to 28 mm and 20-Fr for larger sizes. Its radial strength is lower compared to that of the Melody or SAPIEN valves, That is why it is not the heart valve of choice for stenotic conduits.
Currently, most implants have been performed in Asia, but since December 2019 there is an ongoing clinical trial being conducted in Europe, in which Spain participates. The inclusion criteria are similar to those of any other valve.
Complications and limitations
The complications and limitations of the heart valves described above are:
– Compressions: in approximately 5% of the patients there is risk of coronary compression during the procedure. Large heart valves can distort the aortic root with regurgitation.
– Ruptures: of the conduit, especially if calcified, during predilatation requiring immediate implantation of a covered stent; navigating heart valves is not easy and requires high-support guidewires capable of perforating the PB; during advance and retrieval maneuvers, the tricuspid valve can be damaged causing regurgitation.
Still, mortality rate during the procedure is around 1.4%.21
Fractures were a common thing at the follow-up (12.4%) with the old Melody implants without previous stent implantation and when the risk factors were young age, greater pre- and postprocedural residual gradient, smaller conduit size, proximity to sternum, and presence of recoil after delivery.22 The second most common complication is infectious endocarditis (4.9%), mostly with the Melody, with a higher incidence rate compared to surgical cases. Several hypotheses have been proposed to explain this: damage to the valve during the assembly, no strict observance of sterility measures, previous endocarditis, unsatisfactory hemodynamic results, poor dental hygiene, piercings, tattoos, etc.23
Data from registries24 and multicenter clinical trials on the mid-term evolution of the Melody heart valve and further reinterventions of the valve.25 During a > 5-year follow-up period it is expected that in up to 14.4% to 15% of the cases some procedure will be performed, mostly due to fractures. There is a great variety of indications among the different centers. Actually, in up to 65% of all procedures a valve-in-valve procedure has been performed. This confirms that infectious endocarditis is still the Achilles heel of the Melody valve with a 2.4% incidence rate per patients-year. There are no data available on other types of valves.
PERCUTANEOUS TREATMENT OF PULMONARY BRANCHES
The percutaneous management of PB stenosis has become widely used after the arrival of new materials and technologies. Currently, it is the first option because surgical outcomes are poor. PB stenosis can be congenital, associated with syndromes (Williams-Beuren, Alagille, etc.) or connatal infections like rubella or be part of complex CHD like tetralogy of Fallot, pulmonary atresia or pulmonary artery sling. However, stenosis is the evolutionary or residual result of surgery in these same and other CHD as in the aftermath of the Jatene arterial switch procedure (the Lecompte maneuver) or when it is necessary to place a conduit between the RV and the PB. Percutaneous treatment improves cardiac output and alleviates pressure to the RV, re-balances the distribution of flow to both lungs, improves functional class, exercise capacity (VO2 and VE/VCO2), and eventually the prognosis of patients with univentricular and biventricular physiology. The following are considered criteria for hemodynamic repercussions: gradient ≥ 20mmHg, angiographic stenosis ≥ 50%, RV or pulmonary artery pressure ≥ 60% of systemic blood pressure (biventricular) or asymmetry (≥ 30%) in pulmonary reperfusion as see on the magnetic resonance imaging or the scintigraphy. This flow asymmetry can stop unilateral non-significant stenosis from translating into pressure gradients since we are dealing with a parallel flow.26
Generalities
Balloon angioplasty
Balloon angioplasty is spared for patients with low body weight when the anatomy is not suitable for stent implantation or when the segments will be involved in future surgeries. Immediate restenosis, of up to 50%, due to recoil or extrinsic compression is more common compared to stents. It is a safe procedure with a < 1% rate of major complications. Taking the hilar diameter as the vessel reference, balloons whose critical diameter is 3 times larger compared to the diameter of stenosis are selected without exceeding the double of the reference diameter (figure 5). To be effective the notch needs to go away, and a controlled intimal-medial tear needs to occur for eccentric remodeling, which means that results may not be immediate. The procedure is considered successful with lumen increases ≥ 50% of the minimum diameter, reductions ≥ 20% of RV or systemic pressure or flow increases ≥ 20% towards the target lung.27 Using the latest noncompliant high-pressure balloons and microtome or cutting balloons improves the results of angioplasties that do not respond to conventional balloons or that are especially resistant like those of lobar branches in patients with genetic syndromes. Common cutting balloons are 8 mm in diameter and they need to be placed in the target area through a sheath to avoid damaging the tricuspid or pulmonary valve when advanced or retrieved (figure 6).
Figure 5. Reference diameters in the percutaneous treatment of pulmonary branches.
Figure 6. A: Cutting balloon. B: BIB balloon with mounted covered CP stent. C: BeGrow stent.
Stent angioplasty
Stent angioplasty, described by Mullins in the 1980s, provides structural support and avoids immediate restenosis due to recoil or folding. Its mid- and long-term results are superior to conventional angioplasty. Better profiles and semi-open or open cell designs that allow re-dilatation have made this technique available for younger and thinner patients. However, this has come at the expense of successive re-dilatations needed to adapt to the size of the vessel due to growth or to dilate the origin of jailed branches. Several studies prove that these successive re-dilatations are safe and effective. Closed-cell stents are more stable in the manual crimping and they usually have greater radial strength. They normally navigate on the balloon inside a sheath towards the stenosis to avoid damaging the right valves, stent migration so they can be repositioned before implantation.28 The profile of this sheath is proportional to the diameter of the balloon on which it is mounted. Same sized premounted balloons have a better profile; some models do not even require the use of long introducers for implantation purposes. One of the most commonly used balloons is the BIB double balloon, currently 8 mm to 30 mm in diameter. It consists of 2 concentric balloons where the inflation of the internal one allows us to predict how the stent will behave in the stenosis facilitating sequential expansion, and repositioning if necessary (figure 6). Considering a normal Nakata index of 250 mm2/m2 to 300 mm2/m2, an adult patient of 2 m2 of body surface will need a stent capable of reaching an ideal diameter of 18 mm to 20 mm in each branch. Self-expanding stents improve the profile because they don’t need a balloon for implantation purposes and are not re-dilatable. To this date, they have been approved for other locations like the biliary route or the femoropopliteal axis.29
In general, bare-metal stents are implanted leaving the covered ones for cases where it is necessary to repair the damaged vessel wall or regulate flow using a diabolo-shaped configuration towards one branch or the other or else through a systemic-pulmonary artery shunt (table 3).
Table 3. Stents currently used in pulmonary branches
| Uncovered | Covered | |
|---|---|---|
| Premounted | Formula | BeGraft aortic |
Valeo | Atrium iCAST | |
| Not premounted | AndraStent XL y XXL | CP Covered |
CP stent | ||
Palmaz Génesisbr/>  | Optimus Covered | |
AndraStent (Andramed, Germany): cobalt chromium; semi-open cell design; XL of 8-25 mm and XXL of 10 mm to 32 mm. | ||
New technologies
Some of these new technologies are:
– Drug-eluting balloons: noncompliant balloons with an antiproliferative substance covering like rapamycin analogues or placlitaxel approved to treat peripheral arterial stenosis, but particularly useful to treat in-stent restenosis due intimal proliferation.30
– Bioresorbable stents: they avoid further re-dilatations in growing patients. They can be built with organic polymers or corrodible metal alloys like iron or magnesium. Some studies show inflammatory responses in the vessel wall and doubts surrounding significant restenosis. Still pending approval by the United States Food and Drug Administration, the Pediatric Bioresorbable Stent (480 Biomedical Stent Inc., United States) is the design in the most advanced clinical trial stages so far and has been specifically designed to treat PB stenosis in pediatric CHD.
– Breakable stents: cells with hinges programmed to break with a balloon like the BeGrow (Bentley, Germany) or ready for resorption like the Growth Stent (QualiMeD, Germany) consisting of 2 halves joined by biodegradable sutures that disappear within 5 months, thus facilitating blood vessel growth (figure 6).
Complications
Percutaneous procedures on pulmonary branches are associated with moderate (angioplasty) or high (stent) risk. They are often performed under general anesthesia, with unfractionated heparin at 100 IU/Kg (to a maximum of 5000 IU) and with an activated clotting time ≥ 250 seconds. The most common complications and risk factors are shown on table 4; and they are more common when the procedure is an emergency procedure and when the patient is of a younger age reaching 38% in newborn babies. As a general rule, the support guidewire should be placed in the inferior lobar branch and further guidewires should not be used. Once removed, advancing the sheath again through the recently dilated segment is also ill-advised. Tears or dissections are more common in the traditional balloon, tipically without any clinical repercussions. When there are repercussions, anticoagulation reversal is required by re-inflating the balloon in the leak area, implanting a stent or through surgery. In-stent restenosis is often due to intimal proliferation but also to stent fractures that cause it to lose its structural integrity or due to extrinsic compression. It is less common with semi-open cell designs and with the greater flexibility of self-expanding stents. There are no clear recommendations on antithrombotic treatment after implantation. Endothelization occurs 6 months after implantation and, although thrombosis is rare, the routine clinical practice is using antiplatelet therapy during that time.31
Table 4. Complications and most common risk factors
| Complications | Risk factors |
|---|---|
| Vascular damage | Overdilatation, too rigid guidewire, surgical patches, recent surgery |
| Thrombosis | Cavopulmonary connection, cyanosis, small branches, short activated clotting time, no antiplatelet therapy |
| Stent embolization | Low weight, disproportion, bifurcation, malapposition, emergency, manual crimping |
| Reperfusion edema | Chronic cyanosis, older age |
| Mismatch | Early implantation, non-dilatable design |
| Restenosis | Short overlapping, genetic syndrome, cavopulmonary connection, bifurcation, residual waist, oversizing, external compression, self-expanding stent |
Specific situations
Bifurcations
There are 2 technical options to repair these stenoses without compromising the contralateral branch flow:
– Through the simultaneous implantation of 2 stents, each one mounted on its own guidewire and sheath. Both stents should be of the same size and both balloons should be inflated simultaneously and progressively (figure 1A of the supplementary data).
– By implanting a long open-cell stent from one of the branches towards the pulmonary trunk to later recross towards the contralateral branch with a different guidewire and then implant a second shorter stent (figure 1B of the supplementary data). This technique is useful when we only have 1 venous access or when the implantation of a pulmonary valve with pre-stenting is intended.
Cavopulmonary connection
In the fragile Fontan-type univentricular physiology—a pumpless non-pulsatile pulmonary circuit—the criteria upon which the indication is based are in a lower threshold compared to biventricular physiology. Also, almost any degrees of angiographic stenosis or hemodynamic gradient are significant since they can significantly increase central venous pressure and large asymmetries in flow distribution towards both lungs. Securing the most symmetrical flow distribution possible to both lungs is key to avoiding the formation of arteriovenous fistulas. That is why it may be necessary to reduce the flow of a fistula previously created or towards 1 of the branches through a diabolo-shaped covered stent (figure 2 of the supplementary data). These procedures are complex because of the access routes (femoral, jugular, transhepatic), because patients have been operated on many times, have a higher risk of thrombosis (polyglobulia, non-pulsatile slow flow), sometimes they even have recent surgical beds, are young patients, etc. The PB angioplasty is the most commonly performed procedure—only second to the extracardiac conduit angioplasty—in an extensive modern cohort of patients with total cavopulmonary connection (CPC) both after superior CPC and after completing the inferior CPC (figure 3 of the supplementary data). Stenosis most often occurs in the left PB (the right PB proximal segment originally) due to its longer course, compression of the neighboring ascending aorta, and the presence of lower flow in the stage between the pulsatile Glenn and the total CPC.32
The final size of PB and therefore their flow is directly associated with the long-term success of this physiology and with the patient’s functional class. However, it is often necessary to perform periodic invasive reassessments of the state of the stents previously implanted to adjust them to growth. This is because non-invasive methods may not be sensitive enough. After stent implantation, the clinical practice guidelines published by the American Heart Association recommend anticoagulant therapy for 3 to 6 months.
Postoperative state
The repair of certain CHD is associated with a risk of residual or evolutionary PB stenosis. With the Lecompte maneuver, associated with the arterial switch for the repair of the d-transposition of great arteries, PB stenosis occurs early in up to 28% of patients. On the other hand, pulmonary supravalvular stenosis is the leading cause of reintervention during childhood. Percutaneous treatment is technically challenging because we are dealing with small patients with sometimes recent sutures, in bifurcation, and a compromised space with the SVC and the ascending aorta. (figures 4 and 5 of the supplementary data). This technique is useful when we only have 1 venous access or when the implantation of a pulmonary valve with pre-stenting is intended.
Cavopulmonary connection
In the fragile Fontan-type univentricular physiology—a pumpless non-pulsatile pulmonary circuit—the criteria upon which the indication is based are in a lower threshold compared to biventricular physiology. Also, almost any degrees of angiographic stenosis or hemodynamic gradient are significant since they can significantly increase central venous pressure and large asymmetries in flow distribution towards both lungs. Securing the most symmetrical flow distribution possible to both lungs is key to avoiding the formation of arteriovenous fistulas. That is why it may be necessary to reduce the flow of a fistula previously created or towards 1 of the branches through a diabolo-shaped covered stent (figure 2 of the supplementary data). These procedures are complex because of the access routes (femoral, jugular, transhepatic), because patients have been operated on many times, have a higher risk of thrombosis (polyglobulia, non-pulsatile slow flow), sometimes they even have recent surgical beds, are young patients, etc. The PB angioplasty is the most commonly performed procedure—only second to the extracardiac conduit angioplasty—in an extensive modern cohort of patients with total cavopulmonary connection (CPC) both after superior CPC and after completing the inferior CPC (figure 3 of the supplementary data). Stenosis most often occurs in the left PB (the right PB proximal segment originally) due to its longer course, compression of the neighboring ascending aorta, and the presence of lower flow in the stage between the pulsatile Glenn and the total CPC.32
The final size of PB and therefore their flow is directly associated with the long-term success of this physiology and with the patient’s functional class. However, it is often necessary to perform periodic invasive reassessments of the state of the stents previously implanted to adjust them to growth. This is because non-invasive methods may not be sensitive enough. After stent implantation, the clinical practice guidelines published by the American Heart Association recommend anticoagulant therapy for 3 to 6 months.
Postoperative state
The repair of certain CHD is associated with a risk of residual or evolutionary PB stenosis. With the Lecompte maneuver, associated with the arterial switch for the repair of the d-transposition of great arteries, PB stenosis occurs early in up to 28% of patients. On the other hand, pulmonary supravalvular stenosis is the leading cause of reintervention during childhood. Percutaneous treatment is technically challenging because we are dealing with small patients with sometimes recent sutures, in bifurcation, and a compromised space with the SVC and the ascending aorta. (figures 4 and 5 of the supplementary data). For that reason, traditional balloon angioplasty may be the only effective option in less than half of the cases.33
Other CHD with common residual PB stenosis after surgery are the tetralogy of Fallot, truncus arteriosus, the pulmonary artery sling, etc. and all those that require having to place a conduit between the RV and the PB like the Ross, Rastelli, Yasui, Sano procedures, etc.
The current technological advances made in imaging techniques, materials, and devices has revolutionized the possibilities regarding the percutaneous management of pulmonary trunk, valve, and PB lesions. That is why the indications published in the clinical practice guidelines are being changed.
FUNDING
No funding.
AUTHORS’ CONTRIBUTION
F. Gutiérrez-Larraya Aguado, coordination and final draft revision; C. Abelleira Pardeiro and E.J. Balbacid Domingo partial drafts and provision of figures.
CONFLICTS OF INTEREST
None reported.
SUPPLEMENTARY DATA
Vídeo 1. Gutiérrez-Larraya F. DOI: 10.24875/RECICE.M20000196
Vídeo 2. Gutiérrez-Larraya F. DOI: 10.24875/RECICE.M20000196
Vídeo 3. Gutiérrez-Larraya F. DOI: 10.24875/RECICE.M20000196
Vídeo 4. Gutiérrez-Larraya F. DOI: 10.24875/RECICE.M20000196
Vídeo 5. Gutiérrez-Larraya F. DOI: 10.24875/RECICE.M20000196
Vídeo 6. Gutiérrez-Larraya F. DOI: 10.24875/RECICE.M20000196
Vídeo 7. Gutiérrez-Larraya F. DOI: 10.24875/RECICE.M20000196
Vídeo 8. Gutiérrez-Larraya F. DOI: 10.24875/RECICE.M20000196
REFERENCES
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3. Silvilairat S, Cabalka AK, Cetta F, et al. Echocardiographic assessment of isolated pulmonary valve stenosis:which outpatient Doppler gradient has the most clinical validity. J Am Soc Echocardiogr. 2005;18:1137.
4. Warnes CA, Williams RG, Bashore, et al. TMACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2008;118:e714.
5. Baumgartner H, De Backer J, Babu-Narayan S, et al. 2020 ESC Guidelines for the management of adult congenital heart disease (ACHD). Eur Heart J. 2021;42:563-645.
6. Narang R, Das G, Dev V, et al. Effect of the balloon-annulus ratio on the intermediate and follow-up results of pulmonary balloon valvuloplasty. Cardiology. 1997;88:271-276.
7. McCrindle BW. Independent predictors of long-term results after balloon pulmonary valvuloplasty. Valvuloplasty and Angioplasty of Congenital Anomalies (VACA) Registry Investigators. Circulation. 1994;89:1751-1759.
8. Voet A, Rega F, Van de Bruaene A, et al. Long-term outcome after treatment of isolated pulmonary valve stenosis. Int J Cardiol. 2012;156:11-15.
9. Devanagondi R, Peck D, Sagi J, et al. Long-Term Outcomes of Balloon Valvuloplasty for Isolated Pulmonary Valve Stenosis. Pediatr Cardiol. 2017;38:247-254.
10. Ruckdeschel E, Kim YY. Pulmonary valve stenosis in the adult patient:pathophysiology, diagnosis and management. Heart. 2019;105:414-422.
11. Petit CJ, Glatz AC, Qureshi AM, et al. Outcomes After Decompression of the Right Ventricle in Infants With Pulmonary Atresia With Intact Ven-tricular Septum Are Associated With Degree of Tricuspid Regurgitation:Results From the Congenital Catheterization Research Collaborative. Circ Cardiovasc Interv. 2017;10:e004428.
12. Morgan GJ, Narayan SA, Goreczny S, et al. A low threshold for neonatal intervention yields a high rate of biventricular outcomes in pulmonary atresia with intact ventricular septum. Cardiol Young. 2020;30:649-655.
13. Hogan WJ, Grinenco S, Armstrong A, et al. Fetal Cardiac Intervention for Pulmonary Atresia with Intact Ventricular Septum:International Fetal Cardiac Intervention Registry. Fetal Diagn Ther. 2020;47:731-739.
14. Pragt H, van Melle JP, Verkerke GJ, Mariani MA Ebels T. Pulmonary versus aortic pressure behavior of a bovine pericardial valve. J Thorac Cardiovasc Surg. 2020;159:1051-1059.e1.
15. Stotut KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC guideline for the management of adults with congenital heart disease:executive summary:a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation. 2019;139:e637-697.
16. Boshoff DE, Cools BL, Heying R, et al. Off label use of percutaneous pulmonary valved stents in the right ventricular outflow tract:time to rewrite the label?Catheter Cardiovasc Interv. 2013;81:987-995.
17. Kenny D, Rhodes J, Fleming G, et al. 3-Year outcomes of the Edwards SAPIEN Transcatheter heart valve for conduit failure in the pulmonary position from the COMPASSION multicenter clinical trial. J Am Coll Cardiol Interv. 2018;11:1920-1929.
18. Fleming GA, Hill KD, Green AS, et al. Percutaneous pulmonary valve replacement. Prog Ped Cardiol. 2012;33:143-150.
19. Cao QL, Kenny D, Zhou D, et al. Early clinical experience with a novel self-expanding percutaneous stent-valve in the native right ventricular outflow tract. Catheter Cardiovasc Interv. 2014:84:1131-1137.
20. Kim GB, Song MK, Bae EJ, et al. Successful feasibility human trial of a new self-expandable percutaneous pulmonary valve (Pulsta valve) implantation using knitted nitinol wire backbone and trileaflet α-gal-free porcine pericardial valve in the native right ventricular outflow tract. Circulation Cardiovasc Interv. 2018;11:e006494.
21. Virk SA, Liou K, Chandrakumar D, Gupta S, Cao C. Percutaneous pulmonary valve implantation:a systematic review of clinical outcomes. Int J Cardiol. 2015;201:487-489.
22. Ansari MM, Cardoso R, Garcia D, et al. Percutaneous pulmonary valve implantation:present status and evolving future. J Am Coll Cardiol. 2015;66:2246-2255.
23. Sharma A, Cote AT, Hosking MCK, et al. A systematic review of infective endocarditis in patients with bovine jugular vein valves compared with other valve types. J Am Coll Cardiol Interv. 2017;10:1449-1458.
24. Nordmeyer J, Ewert P, Gewillig M, et al. Acute and midterm outcomes of the postapproval MELODY registry:a multicenter registry of transcatheter pulmonary valve implantation. Eur Heart J. 2019;40:2255-2264.
25. Shahanavaz S, Berger F, Jones TJ, et al. Outcomes of transcatheter reintervention for dysfunction of a previously implanted transcatheter pulmonary valve. J Am Coll Cardiol. 2020;13:1529-1540.
26. Feltes TF, Bacha E, Beekman RH, et al. Indications for Cardiac Catheterization and Intervention in Pediatric Cardiac Disease:A scientific Statement from the American Heart Association. Circulation. 2011;123:2607-2652.
27. Patel AB, Ratnayaka K, Bergersen L. A review:Percutaneous pulmonary artery stenosis therapy:state-of-the-art and look to the future. Cardiol Young. 2019;29:93-99.
28. Hiremath G, Qureshi AM, Prieto L, et al. Balloon Angioplasty and Stenting for Unilateral Branch Pulmonary Artery Stenosis Improve Exertional Performance. JACC Cardiovasc Interv. 2019;12:289-297.
29. Zablah JE, Morgan GJ. Pulmonary Artery Stenting. Interv Cardiol Clin. 2019;8:33-46.
30. Cohen JL, Glickstein JS, Crystal MA. Drug-Coated Balloon Angioplasty:A novel treatment for pulmonary artery in-stent stenosis in a patient with Williams syndrome. Pediatr Cardiol. 2017;38:1716-1721.
31. Giglia TM, Massicotte MP, Tweddell JS, et al. Prevention and treatment of thrombosis in pediatric and congenital heart disease:a scientific statement from the American Heart Association. Circulation. 2013;128:2622-2703.
32. Franco Díez E, Balbacid Domingo E, Arreo del Val V, et al. Percutaneous Interventions in Fontan Circulation. Int J Cardiol Heart Vasc. 2015;8:138-146.
33. Nakanishi T, Matsumoto Y, Seguchi M, et al. Balloon Angioplasty for Postoperative Pulmonary Artery Stenosis in Transposition of the Great Arteries. J Am Coll Cardiol. 1993;22:859-866.
ABSTRACT
For many years, left main coronary artery disease has remained as the last frontier resisting percutaneous coronary intervention. Until recently, the most relevant clinical studies in this regard as well as clinical practice guidelines favored surgical revascularization almost as the only treatment pathway for the management of this condition. The changes that have occurred over the last 10 to 15 years since the appearance of drug-eluting stents and their technological advances have been extraordinary. This, added to the publication of randomized clinical trials that compared both revascularization modalities, has placed percutaneous coronary interventions at a similar level to surgery in a large number of patients. The anatomical, technical, and strategic aspects are essential for the percutaneous management of left main coronary artery lesions given their tremendous clinical variability. In this article we will be reviewing their anatomy, angiography, intracoronary diagnostic techniques, and different percutaneous revascularization strategies. As long as future clinical studies do not definitively favor percutaneous over surgical revascularization or vice versa, individual discussions on each particular case by the heart team and our patients’ preferences should guide our clinical decision-making process.
Keywords: Coronary artery disease. Left main coronary artery. Percutaneous coronary intervention. Coronary artery bypass graft.
RESUMEN
La enfermedad del tronco coronario izquierdo ha permanecido muchos años como la última frontera que se resistía al intervencionismo coronario percutáneo. Hasta hace poco tiempo, los estudios clínicos más relevantes en este campo, así como las guías clínicas, han sido favorables a la revascularización quirúrgica casi como forma exclusiva de tratamiento de esta patología. Los cambios ocurridos en los últimos 10-15 años, desde la aparición de los stents farmacoactivos y su mejora tecnológica, han sido vertiginosos. La realización de estudios aleatorizados que han comparado ambas modalidades de revascularización ha llevado al intervencionismo percutáneo a la altura de la cirugía en un alto porcentaje de pacientes. Los aspectos anatómicos, técnicos y de estrategia son fundamentales en el tratamiento percutáneo de estas lesiones, dada su enorme variabilidad clínica. En tanto los estudios clínicos futuros no se decanten definitivamente a favor de la revascularización percutánea o de la quirúrgica, la discusión individualizada de cada caso en un equipo multidisciplinario y las preferencias de los pacientes deberían guiar la decisión clínica.
Palabras clave: Enfermedad coronaria. Tronco coronario izquierdo. Intervencionismo coronario percutáneo. Cirugía de revascularización coronaria.
Abbreviations: LAD: left anterior descending coronary artery. CABG: coronary artery bypass graft. LCx: left circumflex artery. FFR: fractional flow reserve. IVUS: intravascular ultrasound. LMCA: left main coronary artery. PCI: percutaneous coronary intervention.
INTRODUCTION
Significant left main coronary artery (LMCA) disease is present in 4% to 5% of all coronary angiographies.1 Since the LMCA supplies over 75% of all the myocardial blood flow, the risk associated with its lesions is the highest of all possible coronary lesions. Without revascularization, its prognosis is poor and mortality rate can be up to 37% at 3-year follow-up.2 Revascularization can be surgical or percutaneous, each one with its corresponding advantages and limitations. Assessing anatomic spread correctly, the complexity of coronary artery disease, the patient’s comorbidities, and the operator’s expertise in complex percutaneous coronary interventions (PCI) are key factors when choosing the right revascularization strategy. There are different models and scales to guide the selection of patients. However, none of them has become the leading model yet.3,4
HISTORIC PERSPECTIVE
Coronary artery bypass graft (CABG) has been the standard of care for the management of patients with LMCA disease based on early clinical trials that proved its prognostic benefit in patients assigned to surgery compared to medical therapy.5 Patients with severe LMCA disease were excluded from most of the early clinical trials and, until recently, no specific trial compared the results of surgery vs PCI as one of its endpoints.6,7 Currently, there are randomized clinical trials that have confirmed the utility of the PCI to treat LMCA disease; actually, the American and European clinical guidelines consider it the recommended strategy in certain settings.8,9 Approximately, 50% of this type of lesions are revascularized percutaneously in our setting with an annual 5% increase.10
ANATOMIC CONSIDERATIONS
Anatomically speaking, the LMCA can be divided into 3 portions: ostial portion, mid-portion, and distal portion; the latter is a bifurcation with an angle that is typically wider compared to other coronary bifurcations (> 70°). It supplies at least 75% of the total coronary flow. The LMCA caliber is often 5 mm ± 0.5 mm11 and its mean length is 10.5 mm ± 5.3 mm.12 In up to 30% of the cases it originates a third branch, the ramus intermedius or bisector branch (figure 1).
Figure 1. Main anatomical characteristics of the left main coronary artery (LMCA).
LMCA atherosclerotic disease is often diffuse. When the bifurcation is affected (in 70% of cases) there is also often presence of plaque at the beginning of the left anterior descending coronary artery (LAD) and left circumflex artery (LCx).11 At times, the origin of both the LAD and the LCx is independent from the left coronary sinus without LMCA per se (0.41% to 0.67% of cases).13,14 In 0.03% of patients, the origin of the LMCA is anomalous describing its trajectory between the aorta and the pulmonary artery, a pattern associated with a high risk of sudden death.14,15
LEFT MAIN CORONARY ARTERY ASSESSMENT
Angiography
The clinical practice guidelines of the European Society of Cardiology establish that the revascularization of the LMCA is indicated for patients with angiographic stenoses > 50% and documented myocardial ischemia.16 The practical problem here is that coronary angiography has limitations when evaluating LMCA disease with great intra and interobserver variability.17,18
Some ostial lesions can be overestimated due to catheter-induced overlapping and artifact or the presence of an associated spasm. Consequently, distal lesions may be difficult to assess due to the often diffuse affectation of the bifurcation and lack of a healthy reference vessel. Damping and/or ventricularization of the pressure curve are indirect data of LMCA disease.19
The correct assessment of the severity of LMCA disease is essential given the evidence that functionally nonsignificant lesions have a favorable prognosis without revascularization,20 and the early graft failure seen in nonsignificant lesions.21 In this regard, clinical practice guidelines accept the value of diagnostic imaging modalities like intravascular ultrasound (IVUS) and the pressure guidewire to estimate the severity of LMCA disease.
Intracoronary imaging modalities
The IVUS provides information on the structure and anatomy of the LMCA as well as on the presence of plaque, its spread, composition, and classification. Several studies have determined a minimum lumen area (MLA) > 6 mm² as the cut-off value to establish severity.22,23 The Spanish multicenter, prospective clinical trial LITRO proved that it was safe to delay the revascularizations of intermediate LMCA lesions with MLAs > 6 mm² with favorable results at the 2-year follow-up.24 Also, the IVUS helps us determine whether the coronary ostia of LAD and LCx have significant disease. When revascularization is indicated, the IVUS provides information on the right size of the stent and the best strategy should be based on the anatomy and calcium load of the LMCA and proximal LAD/LCx; in lesions due to previous in-stent restenosis, the IVUS characterizes their etiology and the possible damage to the borders of the stent. The IVUS-guided PCI of the LMCA is beneficial compared to the angiography-guided PCI.25 The need for stent postdilatation and the existence of distal dissection can be assessed too. Also, it can help us determine the need for stent implantation into the lateral branch or exclude the compromise of this branch after implanting a provisional stent.26 Several parameters have been described for the optimization of IVUS-guided PCIs to treat LMCA disease (figure 2 and figure 3). A large metanalysis of patients from several Spanish registries confirmed that the use of IVUS is associated with better clinical progression, fewer deaths and infarctions, and particularly stent thrombosis. These findings are especially significant in LMCA distal lesions.27 Other registries, a few minor clinical trials, and a combined analysis of them all confirm significant clinical benefit from IVUS-guided PCIs performed on the LMCA with fewer deaths, infarctions, and thrombosis.28 The clinical practice guidelines of the European Society of Cardiology consider the use of IVUS to stratify the severity of all LMCA lesions as an indication type IIa B.16
Figure 2. Key points to optimize the percutaneous coronary interventions performed on the ostial and mid-portions of the left main coronary artery through intravascular ultrasound. IVUS, intravascular ultrasound; LAD, left anterior descending coronary artery; LCx, left circumflex artery; LMCA, left main coronary artery; MSA, minimum stent area. (Modified with permission from de la Torre Hernández et al.25.)
Figure 3. Key points to optimize the percutaneous coronary interventions performed on the distal left main coronary artery through intravascular ultrasound. IVUS, intravascular ultrasound; LAD, left anterior descending coronary artery; LCx, left circumflex artery; LMCA, left main coronary artery; MSA, minimum stent area. (Modified with permission from de la Torre Hernández et al.25.)
The utility of the optical coherence tomography (OCT) for the management of the LMCA is somehow more limited, mainly because of the technical difficulty involved in completing contrast filling and the native area of ostial segments. Another downside of the OCT for the management of the LMCA is its limited penetration depth (2 mm to 3 mm) compared to IVUS (4 mm to 8 mm), and since the LMCA often has diameters between 3.5 mm and 4.5 mm the assessment can be wrong. The MLA cut-off value for the management of LMCA lesions with the OCT is still unknown. On the other hand, due to the different image acquisition of both imaging modalities, the thresholds established as cut-off values with the IVUS don’t work with the OCT.
Pressure wire
The pressure guidewire provides valuable information to stratify the severity of LMCA disease.16,29 In order to stop a presumably ostial disease from impacting measurement, pressures need to be equalized and measured using a guide catheter partially «desintubated» from the LMCA. Obtaining hyperemic indices from the LAD and the LCx leads to better overall assessments of the severity of LMCA disease. Also, it secures the decision-making process on the best therapeutic approach. Some authors suggest that IV adenosine is better than intracoronary adenosine to secure the condition of maximum hyperemia.4
Another important aspect when assessing the LMCA with the pressure guidewire is the physiological interdependence of the coronary tree that may change the values of fractional flow reserve (FFR). In particular, the FFR has been reportedly overestimated in the presence of diffuse disease of the LAD and the LCx and underestimated in cases of significant lateral branch disease.30 Therefore, in the presence of concomitant distal branch disease, measuring the FFR during controlled retrieval can be useful.30
Regarding the pathological threshold, it seems that delaying the PCI with FFR values > 0.8 is safe.31 Although the value of other pressure guidewire indices that don’t require hyperemia like the instantaneous wave-free ratio (iFR) has not been fully assessed in the LMCA, a study proved that using the iFR to delay the revascularization of the LMCA is safe.32 Currently, the multicenter clinical trial iLITRO (NCT03767621) is being conducted in Spain. This trial will probably shed light on the utility of the iFR and its pathological threshold in the management of LMCA lesions.
Integrating different techniques
Integrating the IVUS and the pressure guidewire in the assessment of the LMCA of angiographically dubious severity is advised as stated by an international consensus document from the European Association of Percutaneous Cardiovascular Interventions33 (figure 4). Therefore, in ambiguous LMCA lesions, MLAs > 6 mm2 would be indicative of no revascularization, MLAs < 4.5 mm2 to 5 mm2 would be indicative of revascularization, and MLAs between 4.5 mm-5 mm to 6 mm2 would recommend the use of the FFR/iFR indices before making any decision.
Figure 4. Criteria for significant left main coronary artery disease. FFR, fractional flow reserve; MLA, minimum lumen area. (Modified with permission from Johnson et al.33.)
REVASCULARIZATION OF THE LEFT MAIN CORONARY ARTERY
Surgical revascularization
CABG has been the standard of care for patients with LMCA disease since traditional clinical trials confirmed its prognostic benefit in patients randomized to surgery vs medical therapy.5 The CASS registry reported a 4-year survival rate in 88% of operated patients compared to 63% in non-revascularized patients.34 Other studies confirmed that the mortality rate dropped to 65% with surgery.35 This allows a complete revascularization regardless of the characteristics of proximal lesion and technical advances facilitate faster procedures without having to use extracorporeal blood pumps. The main setback is still the non-negligible peri and postoperative morbidity and mortality. Some studies have reported a mortality rate of between 5.5% to 8.5%, a need for ischemia-guided revascularization of 7.1% to 9.4%, and a rate of stroke of 3.1% to 5.1% at the 3-year follow-up.36
Percutaneous revascularization
The arrival of stents improved the results of PCI on the LMCA significantly. However, at the beginning, conventional stents fared worse compared to surgery with mortality rates of 14%, a left ventricular ejection fraction (LVEF) > 40% and 78%, and a LVEF < 40% at the 9-month follow-up.37 With the arrival of drug-eluting stents, the rates of restenosis and adverse events dropped low enough to be able to compare PCI to CABG,38-41 with event-free survival rates at the 1-year follow-up of 98% in patients with LVEF < 40%.38 In patients considered non-eligible for surgery (EuroSCORE > 6 or Parsonnet > 15), the mortality and survival rates without major adverse cardiovascular events were 3.5% and 75.3%, respectively, at the 6-month follow-up.42 These studies already showed that the PCIs performed on the ostial and mid-portions of the LMCA seemed to have a better prognosis compared to those performed on the distal LMCA or that involved bifurcation. The arrival of new antiproliferative drugs, the development of better devices, and the use of new techniques and strategies to treat bifurcation improved results, efficacy, and the good prognosis of the PCIs performed on the LMCA in experienced centers.
Surgical vs percutaneous revascularization
Six landmark randomized clinical trials have compared percutaneous and surgical strategies (table 1). The first ones (LE MANS,43 SYNTAX,44 Boudriot et al.,45 and PRECOMBAT46) were conducted with first-generation drug-eluting stents and reported similar rates of a composite of death, infarction, and stroke for both strategies. The main differences were a higher rate of strokes in the CABG group and a higher rate of new revascularizations after the PCI. The two most recent clinical trials conducted so far, the EXCEL and NOBLE, used second-generation drug-eluting stents and included large cohorts of patients with less complex atherosclerotic disease, which may be indicative of the actual clinical practice.16,47 The difference in results obtained by these studies was very controversial; differences were reported in the definition of endpoint and periprocedural infarction as possible determinants. Actually, unlike the EXCEL, the NOBLE trial excluded periprocedural infarction from the composite of primary events although its inclusion is recommended by the Academic Research Consortium and is part of the universal definition of myocardial infarction. It has been confirmed that periprocedural infarction is associated with a worse prognosis.16 Also, the large difference seen in the rate of stent thrombosis (0.7% in the EXCEL trial vs 3% in the NOBLE) is indicative of the possible influence of the different type of stent used in each of these studies.
Table 1. Main comparative studies between percutaneous and surgical revascularization
| Study | Year | n | Mean SYNTAX score | Distal LMCA lesions | Type of stent | Endpoint(PCI vs CABG) | Secondary endpoints(PCI vs CABG) |
|---|---|---|---|---|---|---|---|
| LE MANS43 | 2008 | 105 | n/a | 58% | Conventional, first-generation covered stents | Change of LVEF at the 1-year follow-up: 3.3% ± 6.7% vs 0.5% ± 0.8%P = .047 |
|
| SYNTAX LM44 | 2010 | 705 | 30 | 61% | Taxus | Death, stroke, AMI or need for revascularization at the 1-year follow-up: 15.8% vs 13.6%; P = .44 |
|
| Boudriot et al.7 | 2011 | 201 | 23 | 72% | Cypher | Death, AMI or need for revascularization at the 1-year follow-up: 19.0% vs 13.9%; P for non-inferiority = .19 |
|
| PRECOMBAT46 | 2011 | 600 | 25 | 64% | Cypher | Death, stroke, AMI, ID-TLR at the 1-year follow-up: 8.7% vs 6.7%; P for non-inferiority = .01 |
|
| EXCEL16 | 2017 | 1905 | 21 | 81% | Xience | Death, stroke or AMI at the 3-year follow-up: 15.4% vs 14.7%:P for non-inferiority = .02; P for superiority = .98. |
|
| NOBLE38 | 2017 | 1201 | 22 | 81% | BioMatrix Other drug-eluting stents | Death, stroke, periprocedural AMI or need for revascularization at the 5-year follow-up: 29% vs 19%; P = .0066. |
|
AMI, acute myocardial infarction; CABG, coronary artery bypass graft; ID-TLR, ischemia-driven target lesion revascularization; LMCA, left main coronary artery; LVEF, left ventricular ejection fraction; N/A, not applicable; PCI, percutaneous coronary intervention. | |||||||
In general, the results of these studies suggest that when complete revascularization is achieved, both surgery and the PCI achieve similar results for the composite of death, infarction, and stroke at the 5-year follow-up.48 However, there is an early benefit for the PCI in terms of periprocedural infarction and stroke that is compensated by the higher risk of infarction at the long-term follow-up. The risk of requiring a new revascularization is evenly higher in patients treated with PCI compared to surgical patients.
Another issue that should be taken into consideration is the correlation between the results of the PCI and the SYNTAX score. The first clinical trials conducted on this topic already suggested that higher scores probably led to a better prognosis with CABG. Some metanalyses have described that, overall, long-term cardiovascular mortality seems to be directly proportional to the angiographic complexity of LMCA disease. Therefore, patients with low SYNTAX scores had a better prognosis with PCI compared to patients with higher scores. Also, patients with high SYNTAX scores showed a non-significant tendency towards a higher 10-year survival rate with surgery compared to PCI.49,50 One of the main setbacks of this score is that it only includes anatomical variables. Currently, there are other scales including angiographical, clinical, and even functional variables, but their utility as long-term prognostic markers of LMCA disease has not been properly studied yet.51
The current clinical practice guidelines on coronary revascularization16 establish the indication for CABG or PCI based on the SYNTAX score (table 2). If complexity is low, the PCIs performed on the LMCA have the same indication as surgery (IA). The PCI is an alternative to surgery in patients with intermediate SYNTAX scores (IIa A) and greater evidence is needed in patients with high SYNTAX scores before clearly recommending PCI.
Table 2. Indication, level, and class of evidence of significant left main coronary artery disease according to the clinical practice guidelines established in 2018 by the European Society of Cardiology8
| Left main coronary artery disease | Surgery | PCI | ||
|---|---|---|---|---|
| Low SYNTAX score (0-22) | I | A | I | A |
| Intermediate SYNTAX score (23-32) | I | A | IIa | A |
| High SYNTAX score (≥ 33) | I | A | III | B |
Patient selection
The European clinical practice guidelines highlight the importance of the heart team in the decision-making process on which revascularization strategy should be used in stable patients with LMCA disease. This team should include clinical and interventional cardiologists and cardiac surgeons. However, in emergent procedures, surgery is not often a viable option due to the delay involved and the progressive worsening of prognosis in relation to ischemic time. Pappalardo et al.52 described in-hospital mortality rates of 21% (basically due to multiorgan failure) in patients with acute myocardial infarction and acute occlusion of the LMCA. However, patients who survived hospitalization and were treated with PCI had a good prognosis with a 1-year survival rate of 89.5%.
In the remaining cases it would be desirable to avoid performing interventional procedures ad hoc after the diagnostic procedure. The different revascularization options should be discussed with the clinical cardiologist, the cardiac surgeon, and especially with the patient. The latter should also be objectively informed of the theoretical pros and cons of every technique and the specific results obtained by the treating center making him part of the decision-making process. Other clinical, anatomic and general factors should be taken into consideration too (table 3). Finally, if performing a PCI on the LMCA is considered the best option, the administration of the right premedication, assessment by the heart team, and procedural planning on the technique and materials that will be used are all associated with higher rates of success.
Table 3. Factors impacting the modality of revascularization of the left main coronary artery
| In favor of PCI | In favor of CABG | |
|---|---|---|
| General factors |
|
|
| Clinical factors |
|
|
| Anatomical factors |
|
|
| Patients’ preferences and needs | ||
CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; DAPT, dual antiplatelet therapy; LMCA, left main coronary artery; PCI, percutaneous coronary intervention. | ||
Since most clinical trials have been conducted in centers with coronary care units, performing PCIs on the LMCA in centers without these units has been controversial. However, since there is evidence of the good outcome of PCIs in centers without these units,53-55 it is widely accepted that PCIs can be performed on the LMCA in these centers safely as long as an experienced medical team is in charge and the necessary technical equipment used. Also, the patient’s informed consent needs to have been collected, and a previous protocol established for urgent transfers to hospitals with coronary care units in the hypothetical case that the patient may require urgent surgery.
Operators and equipment
The PCIs performed on the LMCA should always be considered high-risk procedures. Actually, the experience of the operators is of paramount importance here. There is evidence that patients treated in high volume centers that perform procedures like this regularly have a better prognosis.56
The equipment should guarantee the proper assessment of the LMCA (IVUS, pressure guidewire). All kinds of materials that may be required to perform the angioplasty and handle all possible complications should be available too. Since it is a high-risk procedure, hemodynamic support devices and resources like the intra-aortic balloon pump and the Impella device (Abiomed, United States) are very important.
ANGIOPLASTY OF THE LEFT MAIN CORONARY ARTERY
Prior to performing the procedure, it is essential to conduct a comprehensive analysis of the case to decide on the strategy, access route (radial or femoral), caliber of the introducer sheath (due to the presumable need for the double stenting technique, 7-Fr catheters via femoral access or “7 in 6-Fr” catheters via radial access are advised), and type of guide catheter. Although radial access has replaced femoral access in many cases, the PCIs performed on the LMCA are probably a niche where femoral access should be considered since obtaining the least support possible can be key here. Also, this access facilitates the use of larger caliber catheters and the possibility of quick hemodynamic support device implantation.
Damage to the distal LMCA or bifurcation complicates the procedure with more chances of needing 2 stents and a worse prognosis. Other factors associated with worse outcomes and prognoses are calcifications, smaller LMCA diameters, and the presence of non-ostial disease in the LAD or LCx.57
Wiring and preparation of the lesion
The use of at least 2 angioplasty guidewires (for the 2 main vessels) will be the standard of use in the PCIs performed on the LMCA with notable exceptions like protected LMCA lesions if rotablation is required or in some cases of isolated and ostial LMCA disease. Using 2 guidewires slightly changes the bifurcation angle, facilitates access to the lateral branch and maintains flow towards it. Using 2 guidewires also helps find this lateral branch in cases of occlusion. Actually, some authors advocate the use of the bailout technique with balloon when flow is compromised after stent implantation into the main vessel.58 Predilatation of the main vessel should be avoided if both vessels have not been protected first due to the high risk of changing and moving the plaque, which could occlude the coronary ostium of a branch complicating further catheterizations.
The use of plaque bulking techniques (rotablation or laser, among other) to change the anatomy and facilitate the angioplasty can be considered. LMCA ostial lesions often consist of abundant calcification and large amounts of elastic muscle fibers, which is associated with a risk of elastic retraction of the lesion both after predilatation and stent implantation. On the other hand, the presence of fibrocalcific plaques can condition the use of cutting balloons as the first step and even rotablation, that has proven beneficial in angioplasties of bifurcated LMCAs prior to the implantation of drug-eluting stents.59,60 When the lateral branch shows severe ostial or heavily calcified disease or access to it becomes complicated, predilatation with a non-compliant small-caliber balloon is advised.
Stent selection
Two different scenarios should be looked into when choosing the right stent: whether only the LMCA or the bifurcation should be treated. Treating the LMCA may be justified only in cases of isolated ostial or mid-portion disease. In this situation, a stent of nominal size should be picked that should reproduce the size of the LMCA as much as possible. Another option would be to implant a stent of a smaller size and overexpand it with a high-pressure balloon of the right dimensions. Several platforms achieve large degrees of expansion without jeopardizing the integrity of its structure.61,62 However, there is no clear evidence that stent overexpansion is a safe practice since it is subject to the suboptimal coverage of the intima layer due to metal-to-artery ratio reduction. Also, it can change the polymer or kinetics of the drug-eluting stent.
When the bifurcation should be treated, the stent implanted into the LMCA should cover the proximal portion of 1 of the 2 main vessels. Also, its size should match the proximal diameter of that main vessel. Another important aspect here is having to use the proximal optimization technique (POT) with a non-compliant balloon to adapt the stent proximal caliber to the LMCA. Recrossing towards the lateral branch or using the double stenting technique can be an option too.
Stents implanted into the LMCA are especially prone to proximal deformation because they are in continuous contact with the guide catheter, due to the need for using the POT, and because they scrape against other devices that come through after implantation.63 Therefore, the resistance of every stent to longitudinal compression is a factor that should be taken into consideration during stent selection. Other fundamental characteristics that should be looked into when choosing the ideal stent to perform PCIs on the LMCA are the safety profile and precision provided by the stent (figure 5).
Figure 5. Technical characteristics of the ideal stent to perform percutaneous coronary interventions on the left main coronary artery. LAD, left anterior descending coronary artery; LCx, left circumflex artery; LMCA, left main coronary artery.
Selection of the bifurcation technique
Non-complex bifurcation
When LMCA disease affects 1 bifurcation branch only or the LCx has a small caliber (< 2.5 mm), the best strategy is the provisional stenting technique with a single stent implanted from the LMCA towards the main vessel. In general, the LAD is the main vessel and only in some cases it would be the LCx. Afterwards, the use of the POT with a non-compliant balloon of the right size is routinely advised.
There are times when it is necessary to fully cover the length of the LMCA. In these cases, it is extremely important to be very precise when implanting the stent to treat the coronary ostium properly and avoid any significant stent protrusions into the aorta.
However, there is still controversy over whether it is necessary to always recross it towards the lateral branch and optimize it with the kissing balloon technique in the bifurcation after using the POT if the provisional stenting technique proves insufficient. The kissing balloon technique should be used with suboptimal final outcomes in the lateral branch, when the main vessel selected is the LCx, and when the future need for a PCI on the lateral branch cannot be discarded.4
Complex bifurcation
When disease affects both bifurcation branches significantly, the use of the double stenting technique should be considered. However, since different registries report that the rates of restenosis and new revascularizations are lower with the single stenting technique,38,64-66 the early approach in many centers and in most complex bifurcations is often using the provisional stenting technique with the possibility of finishing using the double stenting technique, if necessary. With suboptimal results, the expert committee of the European Bifurcation Group recommends using double T stenting, the T and small protrusion (TAP) or the culotte technique as the bailout strategy after provisional stent implantation.67 Once the second stent has been implanted into the lateral branch, individual dilatation in both branches is advised using non-compliant balloons to secure the ostial expansion of the stent of the LAD and the LCx followed by the kissing balloon technique. If it takes over a significant portion of the LMCA, a new proximal dilatation (re-POT) should be performed to optimize the result.
When the double stenting technique is used right away, this selection is often based on different factors: anatomical and angiographic variables, location of the lesion, intracoronary imaging modalities, damage to the LAD and LCx coronary ostia, clinical situation, and even the operator’s skills in each technique. To this day, we still do not have enough evidence to know which is the best technique. Several algorithms and therapeutic strategies have been suggested based on the parameters mentioned above like the ones proposed by Fajadet et al.68 or De Maria and Banning.69 However, none of them has come out victorious maybe due to the huge variability of clinical and angiographic situations and the different experience reported by the different centers. The crush, modified crush, and culotte techniques are still the most widely used today. The double kissing crush technique seems to have good results as it is associated with a lower rate of target lesion failure or stent thrombosis at the 3-year follow-up (figure 6).70
Figure 6. Example of double kissing crush stenting technique. 1: baseline angiography. 2: stent implanted towards the circumflex artery. 3: first kissing balloon inflation. 4: stent implanted towards the left anterior descending coronary artery. 5: second kissing balloon inflation. 6: angiography with final outcome.
Result optimization
The IVUS, the OCT, and the guidewire pressure optimize the results of the angioplasties performed on the LMCA. There is evidence that the suboptimal result of these angioplasties performed on the LMCA is associated with a worse clinical prognosis.71 Although the OCT shows the aforementioned limitations (limited penetration depth compared to the IVUS, possible inadequate filling), the truth is that both imaging modalities can detect significant findings like stent underexpansion, strut malapposition, border dissection, and degree of lateral branch involvement, which could require result optimization.
The imaging modality we have more evidence of in the optimization of angioplasty results of the LMCA is also IVUS that has an associated net clinical benefit.26,72,73 The protocolized use of IVUS for optimization purposes seems to additionally improve the prognosis of these patients.30 However, the ongoing clinical trial OPTIMAL (NCT04111770, Optimization of left main percutaneous coronary intervention with intravascular ultrasound randomized controlled trial), that will be recruiting 800 patients, will shed light on the prognostic effect of using IVUS in PCIs performed on the LMCA compared to angiography alone.
On the other hand, several studies have been conducted on the pressure guidewire and its value as a predictor of events in cases of provisional stent implantation by estimating the flow reserve towards the lateral branch.74
MEDICAL THERAPY AFTER PERCUTANEOUS CORONARY INTERVENTION AND FOLLOW-UP
Although angioplasties performed on bifurcations are a predictor of events,54,75 currently, there is no evidence available to recommend a specific antiplatelet therapy in angioplasties performed on the LMCA. Therefore, treatment should be administered based on each patient’s clinical presentation and ischemic and hemorrhagic risk profile. However, we should bear in mind that implanting a stent into the LMCA and performing a PCI on a bifurcation, especially when 2 stents are used, are criteria that add more ischemic risk to the profile of these patients.76-79
The reappearance of suggestive symptoms or documented ischemia justifies an invasive approach. The review coronary angiography performed at the 1-year follow-up in patients with angioplasty on the LMCA has a level IIB C indication according to European clinical practice guidelines,16 and is not justified in all cases. The randomized clinical trial ANGELINE (Angiographic evaluation of left main coronary artery intervention) (NCT04604197) will bring more evidence on the potential advantages of the systematic angiographic review.
CONCLUSIONS
The assessment of LMCA lesions is complex, which is why acquiring different angiographic views and using imaging modalities like IVUS or pressure guidewire is advised.
Currently, the SYNTAX score, the possibility of complete revascularization, and the patient’s comorbidities are the main criteria that should guide the selection of percutaneous or surgical revascularization.
Regarding the PCIs performed on LMCA lesions, there are 2 different categories: isolated ostial or mid-portion LMCA lesions (technically easier to treat and with an excellent prognosis), and bifurcation lesions (with a more complex approach).
Optimizing the PCIs performed on the LMCA is essential using intravascular ultrasound and techniques and stents backed by the highest level of evidence in this setting followed by the proper pharmacological cover.
In conclusion, there is no doubt that PCIs performed on LMCA lesions crossed their own particular Rubicon a long time ago. Alea jacta est (which is Latin for “the die is cast”) and, in the future, new randomized clinical trials on surgical or percutaneous revascularization and technical advances in both modalities will favor one over the other. In the meantime, revascularizations based on every individual patient and in close collaboration with the heart team should guide the routine practice of clinical cardiologists and interventional and cardiac surgeons.
FUNDING
No funding declared.
CONFLICTS OF INTEREST
The authors declared no conflicts of interest regarding the content of this manuscript.
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77. Colombo A, Bramucci E, Sacca S, et al. Randomized study of the crush technique versus provisional side-branch stenting in true coronary bifurcations:the CACTUS (Coronary Bifurcations:Application of the Crushing Technique Using Sirolimus-Eluting Stents) Study. Circulation. 2009;119:71-78.
78. Hildick-Smith D, De Belder AJ, Cooter N, et al. Randomized trial of simple versus complex drug-eluting stenting for bifurcation lesions:the British Bifurcation Coronary Study:old, new, and evolving strategies. Circulation. 2010;121:1235-1243.
79. Maeng M, Holm NR, Erglis A, et al. Long-term results after simple versus complex stenting of coronary artery bifurcation lesions:Nordic Bifurcation Study 5-year follow-up results. J Am Coll Cardiol. 2013;62:30-34.
Corresponding author: Sección de Hemodinámica, Servicio de Cardiología, Hospital General Universitario de Ciudad Real, Obispo Rafael Torija s/n, 13005 Ciudad Real, Spain.
E-mail address: drlozano68@gmail.com (F. Lozano Ruiz-Poveda).
ABSTRACT
Percutaneous coronary intervention (PCI) plays a key role in the management of patients with obstructive coronary artery disease. Besides, depending on the patients’ clinical presentation, characteristics, comorbidities, and coronary anatomy, an increasing number of patients will undergo a high-risk PCI. Left ventricular assist devices, as the intra-aortic balloon pump, TandemHeart, Impella, HeartMate PHP, and extracorporeal membrane oxygenation are useful tools to provide circulatory support for high-risk PCIs. Some studies and trials have assessed its impact on this clinical scenario with controversial results. This review provides an overview on the scientific evidence available on the use of left ventricular assist devices and their potential role in high-risk PCI.
Keywords: Intra-aortic balloon pump. Left ventricular assist device. High-risk percutaneous coronary intervention. Cardiogenic shock. Right ventricle.
RESUMEN
La intervención coronaria percutánea (ICP) desempeña un papel fundamental en el tratamiento de los pacientes con enfermedad coronaria obstructiva. De ellos, un porcentaje significativo se someterán a un procedimiento de alto riesgo, en función de la presentación clínica, las características del paciente y su anatomía coronaria. Los dispositivos de asistencia ventricular izquierda, como el balón intraaórtico de contrapulsación, el dispositivo TandemHeart, el Impella, los dispositivos HeartMate PHP y las técnicas de oxigenación veno-arterial con oxigenador extracorpóreo de membrana (ECMO), son herramientas empleadas para proporcionar soporte circulatorio en la ICP de alto riesgo, con un impacto creciente en la práctica clínica. Existen numerosos trabajos en la literatura científica sobre su empleo en este escenario, con resultados controvertidos. Esta revisión proporciona una visión general de la evidencia disponible sobre el empleo de los distintos tipos de dispositivos, así como de su potencial papel en la ICP de alto riesgo.
Palabras clave: Balón intraaórtico de contrapulsación. Dispositivo de asistencia ventricular izquierda. Intervencionismo coronario percutáneo de alto riesgo. Shock cardiogénico. Ventrículo derecho.
Abbreviations: AMI: acute myocardial infarction. CHD: coronary heart disease. ECMO: extracorporeal membrane oxigenator. IABP: Intra-aortic balloon pump. LMCA: left main coronary artery. LVAD: left ventricular assist device. PCI: percutaneous coronary intervention.
INTRODUCTION
In the Western world, coronary heart disease (CHD) is a problem of public health. It is estimated that in the US population over 20, 15.5 million people suffer from CHD and nearly 635 000 will suffer from a new acute coronary event each year.1 The percutaneous coronary intervention (PCI) as the way to treat this condition is still growing exponentially and it is currently the treatment of choice for revascularization purposes,1-3 except for certain patients with multivessel or highly complex disease.4,5 The has a class I recommendation for the management of patients with acute coronary events and it is the first-line therapy in 3 clinical settings: refractory angina to medical therapy, cardiogenic shock as a complication of the acute myocardial infarction (AMI), and ST-segment elevation acute coronary syndrome.3,4
HIGH-RISK PERCUTANEOUS CORONARY INTERVENTION
The criterion to define a PCI as a high-risk PCI is not well-established, but there is a series of characteristics that give it a high periprocedural risk profile that can be divided into 3 groups: patient-specific, lesion-specific, and clinical presentation- specific.6-9
Patient-inherent factors are old age, diabetes mellitus, chronic kidney disease, previous myocardial infarction, severe peripheral vascular disease, and the presence of left ventricular systolic dysfunction defined as a value < 30%-35%.9,10
The factors dependent on the characteristics of the coronary lesion are left main coronary artery disease (LMCA)—unprotected—, ostial disease or in bifurcations, lesion to the saphenous vein bypass graft, presence of abundant calcification, and chronic occlusions.11,12 Finally, clinical presentation plays a role in the prognostic of these patients in such a way that those with a cardiogenic shock or hospitalized with an acute coronary syndrome have a higher risk of adverse events during the PCI.13
We should mention that cardiogenic shock is the leading cause of death associated with the AMI with a prevalence between 5% and 15%.13,14 There is growing evidence that the prognosis of patients with AMI complicated with cardiogenic shock could substantially improve with early PCIs and primary angioplasty.15,16
PERCUTANEOUS CIRCULATORY ASSIST DEVICES
Left ventricular assist devices (LVAD) are used to provide hemodynamic support during high-risk PCIs. These devices include the intra-aortic balloon pump (IABP), the TandemHeart device (CardiacAssist, United States), the Impella device (Abiomed, United States), the HeartMate PHP devices (St. Jude Medical, United States), and veno-arterial oxygenation techniques with extracorporeal membrane oxygenation (ECMO).17 Their main characteristic are comparatively described and shown on table 1.
Table 1. Comparison of the different type of left circulatory assist devices based on their baseline characteristics
| Device | Pump action mechanism | Cardiac chamber of action | Vascular access | Flow |
|---|---|---|---|---|
| IABP | Counterpulsation | LV | 8-9 Fr | 1 L/min |
| ECMO | Centrifugal | Biventricular | Venous (15-22 Fr) Arterial (15-21 Fr) | > 4.5 L/min |
| TandemHeart | Centrifugal | LV, RV or biventricular | Venous (15-17 Fr) Arterial (21-Fr) | 4.5 L/min |
| Impella 2.5 | Axial | LV | 12-Fr | 2.5 L/min |
| Impella CP | Axial | LV | 14-Fr | 3.33 L/min |
| Impella 5.0 | Axial | LV | 21-Fr | 5 L/min |
ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; LV, left ventricle; RV, right ventricle. | ||||
The intra-aortic balloon pump
Since it was first introduced back in the 1970s, the IABP has become a circulatory assist device for several indications
Their capacity to improve coronary flow,18,19 improve systemic flow by an additional increase of cardiac output of 0.5 L/min,14,20,21 and reduce the myocardial oxygen consumption22 recommends it use in all those patients in whom coronary and systemic flow needs to be increased.
Recently, in the US clinical practice guidelines,3 the use of IABPs has gone from a class I a to a class II b recommendation in the cardiogenic shock setting as a complication of AMI. The European guidelines23 give IABPs a class III recommendation. This has to do with the studies that question the value of IABP as a factor worth of prognostic impact.24 The IABP SHOCK study compared the use of the IABP after PCI and the standard approach with inotropes and vasoactive amines without confirmation of short-term benefits in mortality rate.25 These findings were backed after the publication of the IABP-SHOCK II study that found no differences in 30-day mortality rate24 or all-cause mortality rate at the 12-month follow-up26 in patients with AMI complicated with cardiogenic shock.
A meta-analysis suggests that the preoperative use of IABP reduces preoperative mortality and the 30-day mortality rate in high-risk patients scheduled to undergo elective surgery of myocardial revascularization.27-32 Other authors think that the use of IABPs does not impact mortality in patients with AMI regardless of whether they show cardiogenic shock or not.14,33,34
These contradictory results set the foundations of new research studies.
Current situation in PCI procedures
The IABP has been used over decades in high-risk PCIs thanks to its circulatory support capabilities.9,35-38 A series of studies compared its elective implantation in this context with its use as a bail-out strategy in stable patients eligible for a high-risk PCI. These studies suggest that the elective implantation of an IABP prior to the procedure is associated with fewer adverse events during the PCI39,40 with a tendency towards fewer major adverse cardiovascular events. Mishra et al.38 reported that the prophylactic implantation of an IABP prior to a high-risk PCI was associated with a higher survival rate during the hospital stay and at the 6-month follow-up compared to its implantation as a bail-out strategy due to the development of hemodynamic compromise during the procedure. All of it happened at the expense of a high risk from this group of complications associated with bleeding complications.41 Although these data are relevant they all come from retrospective studies.
Back in 2010, Perera et al.39 conducted a prospective, multicenter, randomized, and controlled clinical trial on coronary interventions assisted with intra-aortic balloon pumps (BCIS-1). This study randomized 301 patients with CHD and a left ventricular systolic dysfunction < 30% to receive, or not, an elective IABP. The primary endpoint was the presence of cardiovascular adverse events at the 28-day follow-up, which occurred in 15.2% of the patients where the IABP was implanted electively compared to 16% of the patients where the IABP was not scheduled. The elective use of the IABP was associated with fewer bleeding and local complications compared to its bail-out use in the group of patients without scheduled implantations. These results are consistent with those of a meta-analysis recently published.34
Based on the results from clinical trials, the use of IABPs in high-risk PCIs has been going down.13,41 At the same time, the development and use of other LVADs in this context has been going up.42
TandemHeart
The TandemHeart (figure 1) is an external temporary mechanical circulatory support device capable of supplying a continuous flow 4 L/min.43 It includes 3 subsystems and it is the only device designed to enter the interatrial septum through a 21-Fr cannula that is allocated in the left atrium. The oxygenated blood is pumped out of the left atrium and then returned through a centrifugal pump that provides continuous flow into the femoral artery (through a 12-Fr cannula) or the iliac artery (through a 5-17-Fr cannula).
Figure 1. Scheme of the functioning of the TandemHeart device with femoral peripheral access. Oxygenated blood drainage by transseptal puncture of the left atrium that comes back though the femoral artery.
A cohort study conducted by Thiele et al.43 among 18 patients with cardiogenic shock post-AMI confirmed significantly better hemodynamic parameters after IABP implantation at the expense of a series of complications associated with the insertion and maintenance of the catheter with a 44% 30-day overall mortality rate. This study also showed that LVADs can be implanted quickly in less than 30 minutes.
Other studies have compared the efficacy of TandemHeart vs IABP for the management of cardiogenic shock such as the ones conducted by Thiele et al.42 and Burkhoff et al.44. These studies showed the capacity of the TandemHeart device to improve the patients’ hemodynamic situation assuming that there is still a risk of complications associated with the device.
Current situation in PCI procedures
The first case ever reported of a TandemHeart device used in a high-risk PCI was documented by Vranckx et al.45. Since then, several retrospective studies have been conducted in an attempt to analyze its use. One of them included 9 patients with an LMCA lesion who were not eligible for surgery. This study reached a 100% success rate in the PCI.46 Four out of these 9 patients developed vascular access complications, 2 of which required vascular surgery due to the presence of lower-limb ischemia. The 6-month survival rate was 88.5% compared to 89.5% in the overall population with LMCA disease in the same hospital.47,48
Then, Aragon et al.49 analyzed the use of the TandemHeart device in 8 patients who underwent a high-risk PCI and found that hemodynamic improvement can be achieved early with angioplasty success rates close to 100% and no immediate complications after the PCI.
Back in 2012, Alli et al.50 conducted a retrospective study that analyzed 54 patients who underwent a PCI under TandemHeart support between 2004 and 2009 with a PCI success rate of 97% (62% of the patients had multivessel or LMCA disease). The overall 30-day survival rate was 90%, and it was kept for 6 months. However, the rate of vascular complications is significant (13%).50,51
Impella
Impella devices (figure 2) use a catheter via femoral access that crosses the aortic valve that is allocated in the left ventricle where it pumps out oxygenated blood that is then returned to the ascending aorta. There are different models available: Impella 2.5, Impella CP, and Impella 5.0 supplying 2.5, 4, and 5 L/min of flow, respectively.
Figure 2. High-risk percutaneous coronary intervention with circulatory support with the Impella 2.5 device. A and B show the correct location of the device while crossing the aortic valve.
An early study conducted by Seyfarth et al.52 that compared the Impella 2.5 device and the IABP in 25 patients with cardiogenic shock post-AMI confirmed that the Impella 2.5 device provided better hemodynamic support compared to the IABP. However, it also had a higher rate of transfusions and hemolysis compared to the IABP, but no differences were seen in the 30-day mortality rate (around 46%). The EUROSHOCK registry53 included 120 patients with cardiogenic shock post-AMI who received circulatory support with an Impella 2.5 device. This registry confirmed that it is a real option resulting in better plasma lactate concentrations at the expense of a red blood cell concentrate transfusion rate of 24% and a 4.2% need for hemostatic surgery.
In this cohort study, the 30-day mortality rate was 64% and it was attributed to the high percentage of patients with clinical presentations of cardiorespiratory arrest.
Current situation in PCI procedures
Back in March 2015, the US Food and Drug Administration approved the use of the Impella 2.5 device as a LVAD in high-risk PCIs, whether elective or urgent. This followed the results of several studies that back the safety of the device in this context.54
The Europella registry55 included 144 patients who underwent high-risk PCIs under Impella 2.5 support. The primary endpoint was the development of events at the 30-day follow-up: death, major bleeding (requiring transfusion or surgery), AMI, need for urgent revascularization surgery or stroke; it also included safety events associated with the device.
In the American USpella registry56 of 175 patients with similar endpoints (except for bleeding, that was considered a secondary endpoint), the primary endpoint of death occurred in 7 patients (4%), while in the Europella registry it occurred in 8 (5.5%). Mortality results were better than the ones estimated by the STS score—predictor of surgical mortality—suggestive that support with Impella devices in this type of PCIs is a reasonable option. Complications associated with the removal of the device were reported in 8 (5.5%) and 17 (9.7%) patients, respectively. Transfusions were needed in 1 (0.7%) and 3 (1.7%) cases due to major vascular complications.
The Impella CP device also has a retrospective analysis that was consistent with previous outcomes and found better survival rates in patients with cardiogenic shock due to AMI compared to the Impella 2.5 device.57
HeartMate PHP
Same as it happens with the Impella device, the HeartMate PHP uses an axial flow circulatory support system to pump blood out the left ventricle and into the ascending aorta; the main difference here is the existence of a self-expanding cannula that expands itself when it crosses the aortic valve and is implanted via femoral access with a 13-Fr/14-Fr sheath. The cannula is then expanded up to 24-Fr when it reaches the right position through the aortic valve supplying flow of up to 4 L/min.58 However, since February 2017 its use and the clinical trials that were being conducted like the SHIELD II trial (NCT02468778) have been suspended temporarily due to minor errors in its design.
Extracorporeal membrane oxygenation
ECMO can provide cardiopulmonary support similar to the extracorporeal circulation system used during cardiac surgery. Its use is well documented in the pediatric population in the severe heart or respiratory failure setting.59,60
Veno-arterial ECMO includes a circuit with cannulas of venous and arterial blood, a centrifugal pump, and a membrane oxygenator. It can be implanted via peripheral (often femoral) or central access and requires a median sternotomy.
Deoxygenated blood is drained through the venous cannula (20-Fr) from the right atrium towards the membrane oxygenator where gas exchange takes place. Oxygenated blood returns to the patient through the arterial cannula (17-Fr).
Although it is the only device capable of providing full circulatory and respiratory support, it can increase left ventricular afterload and parietal stress (due to several filling pressures), which may have negative consequences for the myocardial oxygen demand.61-64
Current situation in PCI procedures
The use of ECMO in the severe heart or respiratory failure setting has gone up 433% during the 2006-2011 period.65 Still, the experience in its use as a mechanical circulatory support system for high-risk PCIs is limited and only small retrospective studies and series of cases have been published to this day.66-68
Back in 1989, Taub et al.65 documented 7 cases of successful use of ECMO in high-risk angioplasties. The rate of complicated hematomas was high (6 patients of whom 4 required a blood transfusion); we should mention the retroperitoneal hematoma as a complication that caused the patient’s death.
In order to study the use of ECMO in high-risk PCIs, Toma-sello et al.69 published their own experience in a prospective study that included 12 patients with complex of high risk to be surgically revascularized without cardiogenic shock or cardiac arrest with veno-arterial ECMO implantation prior to the PCI. All patients tolerated the procedure and there was only 1 complication in the vascular access (1 hematoma did not require blood transfusion). No deaths or AMIs were reported at the 6-month follow-up, suggestive that ECMO can be a safe alternative in this context.
IABP vs other LVADs in PCI procedures
Several clinical trials have conducted direct comparisons between the IABP and other LVADs. The PROTECT II trial11 compared the Impella 2.5 device to the IABP in high-risk PCIs. This was a multicenter, prospective study of 452 patients eligible for a high-risk PCI (defined as LMCA disease and left ventricular ejection fraction < 35% or multivessel disease with left ventricular ejection fraction < 30%). They were randomized to receive circulatory support with the Impella 2.5 device or IABP during the procedure. Patients with recent AMI were excluded from the study. The 30-day primary endpoint was a composite of major cardiovascular events and mortality. The Impella 2.5 device provided better hemodynamic support compared to the IABP without statistically significant differences in the primary endpoint: 35.1% in the Impella 2.5 group and 40.1% in the IABP group (P = .227).
Patel et al.70 conducted a cross-sectional study during the 2008-2012 period. The study analyzed patients who underwent PCI and received circulatory support with an IABP or other LVADs (Impella, TandemHeart or a combination of IABP plus LVAD) and recorded 18 094 procedures (93% with the IABP, 6% with the Impella o TandemHeart device, and 1% with IABP plus LVAD). In the first place, the patients assisted with a LVAD were older and had more comorbidities (arterial hypertension, diabetes mellitus, renal failure, pulmonary disease) compared to those assisted with the IABP. The overall mortality rate was 19.8% (20.1% with the IABP, 12% with the LVAD, and 41% with the combination of IABP plus LVAD) and the overall rate of complications was 35.5% (36% with the IABP, 26% with the LVAD, and 52% with the combination of IABP plus LVAD). The use of the IABP was associated with a higher rate of cardiovascular (9% vs 4%) and respiratory complications (19 % vs 11%), while the use of other LVADs was associated with a higher rate of vascular complications (8.6% vs 5.5%). A subgroup analysis was conducted based on the presence, or not, of cardiogenic shock or AMI. The main conclusion was that compared to the IABP, the use of the LVAD was a predictor of a lower rate of complications and mortality only in the group of patients without AMI or cardiogenic shock.
Khera et al.71 conducted a study similar to the previous one in the 2004-2012 period but without patients who received support with both devices (combination of IABP plus other LVADs). A total of 26 556 patients underwent high-risk PCIs under IABP (96%) or LVAD (4%) support. Seven per cent of those who received LVAD support had cardiogenic shock and 2.2%, AMI. Also similar to the previous study, the authors found that patients who received LVAD support were older and had more comorbidities, but a lower rate of AMI, cardiogenic shock, and cardiorespiratory arrest compared to the group of patients who received the IABP; no significant differences were seen in the in-hospital mortality rate.
The IMPRESS trial,72 published back in October 2016, randomized 48 patients hospitalized due to ST-segment elevation and secondary acute coronary syndrome and secondary cardiogenic shock to receive support with the Impella CP device or the IABP in high-risk primary PCIs; this was the first study ever conducted with characteristics like these ones. No differences were found in the primary endpoint of death and 30-day cardiovascular events (46% mortality rate in the Impella CP group vs 50% in the IABP group; P = .92) or in the all-cause mortality at 6 months (50% in both groups), but there was a higher rate of vascular complications in the group that received support with the Impella CP device (major bleeding: 33% vs 8%) due to the larger caliber of the cannula used by this device (14-Fr vs 7.5-Fr).
The results published by Koen et al. back in 2019 are interesting too.73 This retrospective, single-center study analyzed the progression and prognosis of patients treated with high-risk PCI during the 2011-2018 period based on whether they received mechanical circulatory support or not. The primary endpoint was a composite of periprocedural mortality (< 24 hours), cardiac arrest, need for vasoactive drugs, need for circulatory support as a bail-out strategy, endotracheal intubation, and peripheral ischemia. One-hundred and ninety-eight patients treated with high-risk PCIs were recruited. Sixty-nine (35%) of these benefited from LVAD support: 18 with the Impella CP device, 25 with the HeartMate PHP device, and 26 with the Pulsecath iVAC 2L device (PulseCath BV, The Netherlands; it is a transfemoral pulsatile ventricular assist device that enables a cardiac output of up to 2 L/min). In this study the rate of the rate for the primary endpoint was 20% in the group of patients without circulatory support compared to 9% in the group that received periprocedural circulatory support.
Amin et al.74 published a retrospective study including 48 306 patients treated with high-risk PCIs circulatory suppport (43 524 with the IABP and 4782 with the Impella device). This study was conducted throughout a 13-year period (2004- 2016) in 432 hospitals from the United States. A pre-Impella era until 2007 was identified (the Impella 2.5 device was approved by the US Food and Drug Administration to be used in high-risk PCIs in 2008). The use of the Impella device grew exponentially until 2016. In the group of patients received support with the Impella device, the authors saw more adverse events in the form of death, bleeding complications, and strokes. Still, these patients were not in a more critical situation compared to the group of patients that received IABP support.
These findings prompted an interesting discussion. Yet despite the sample size, there are different factors that may explain such results, but they seem insufficient to stop recommending the use of this device in patients treated with high-risk PCIs. In the first place, this was a retrospective study with substantial differences in the experience and volume of cases managed in each center. Similarly, the use of the new antiplatelet therapies—that grew significantly from 2009—may partially justify the higher rate of bleeding complications reported.
On the other hand, the authors did not provide a detailed description of the characteristics of the patients’ coronary anatomy (only a higher prevalence of multivessel disease, bifurcation lesions, and chronic occlusions was reported in the Impella group). They did not report either on the rates of PCI success, the patient’s clinical and hemodynamic tolerance to the procedure, the main reason for using a LVAD in this context or the causes for the mortality seen. The authors clarify that patients with the Impella device were not more critical since the rate of cardiogenic shock and need for invasive mechanical ventilation was lower compared to patients with the IABP. However, after a thorough review of the results, it stands out that in the Impella group there was a higher prevalence of previous heart failure, chronic obstructive pulmonary disease and chronic kidney disease, comorbidities that may be behind the results seen. Also, we should mention that the average hospital and ICU stays combined were lower in the group that used the Impella device as the LVAD.
For these reasons, taking the above-mentioned limitations into consideration, and yet despite the study sample size and its surprising results, some associated confounding factors were seen, which is why it may be risky to stop recommending the use Impella devices in the high-risk PCI setting.
Right ventricular failure in patients implanted with a LVAD. Circulatory support devices
Generally speaking, right ventricular (RV) failure occurs in nearly 20% to 50% of the patients after a LVAD implantation procedure.75 However, no uniform requirements to define RV failure are to be found in the medical literature (table 2). Its pathogenesis is multifactorial. Left ventricular unloading by LVADs induces a loss of septal contribution to the right function (septal contraction represents 60% of the power of RV contractility).76
Table 2. Definitive criteria for right ventricular failure after left ventricular assist device implantation
| Postoperative support with inotropes for over 14 days |
| Use of inhaled nitric oxide for over 48 hours |
| Need for inotropic treatment at the hospital discharge |
| Right circulatory support |
| 2 or more of the following hemodynamic parameters: |
| Mean arterial pressure < 55 mmHg |
| Central venous pressure > 16 mmHg |
| Mixed venous saturation < 55% |
| Cardiac index (flow supplied by LVAD) < 20 L/min/m2 |
| Inotropic support score > 20 U |
LVAD, left ventricular assist device. |
Due to the significant morbimortality associated, the right selection of patients who are eligible for LVAD implantation is key. These are some predictors of RV failure:77
– Right atrial pressure prior to implantation > 20 mmHg.
– Transpulmonary gradient prior to implantation > 16 mmHg.
– Sudden drop (> 10 mmHg) of the pulmonary arterial pressure after implantation.
– Central venous pressure/pulmonary capillary wedge pressure ratio > 0.63.
– Tricuspid regurgitation grade > III prior to implantation.
– RV short axis/long axis ratio > 0.6.
– Need for circulatory support prior to LVAD implantation.
– Hypertransaminasemia, hyperbilirubinemia or renal im- pairment.
– Need for invasive mechanical ventilation prior to im- plantation.
– Right ventricular free wall global longitudinal strain < –9.6%.
The management of RV failure is basically preventive. The proper selection of patients eligible for LVADs is key as well as optimizing their RV preload and afterload situation in order to reduce central venous pressure. As general measures, it is essential to perform anti-infective prophylaxis, avoid cardiac arrhythmias, and schedule protective mechanical ventilation towards the RV (with low positive end-expiratory pressure). Dobutamine, adrenaline, and milrinone are the main inotropic agents used to treat RV failure after LVAD implantation and they can be associated with drugs used to reduce pulmonary arterial pressure.
Circulatory assist devices have a role in the clinical setting too. Veno-arterial ECMO—already described in this manuscript—mimics the RV function. Another member of the Impella family is the Impella RP model that has a single 22-Fr cannula that pumps blood out of the inferior vena cava and into the pulmonary artery and supplies flow at a rate of 4 L/min with promising results in the RECOVER RIGHT trial.78 This study recruited 30 patients with acute RV failure (after LVAD implantation and due to an AMI with right ventricular involvement).
Economic impact of the use of LVADs
The economic impact left by the technical advances made in the percutaneous management of cardiovascular heart disease is growing. An analysis of the costs involved in the healthcare provided in the PROTECT II trial shows that hospitalization related costs were higher in the Impella group compared to the IABP group ($47 667 vs $33 684). A difference that would not only be explained by the cost of the device.79 In contrast, the costs derived from the hospital stay and rehospitalizations were lower in the Impella 2.5 device group ($11 007 vs $21 834).
CONCLUSIONS
The future will shed light on the true role of LVADs in the cath lab. All of these devices are used to improve the cardiac output, mean arterial pressure, coronary perfusion by reducing the pulmonary capillary wedge pressure in patients with a reduced cardiac reserve.
Yet despite the controversial results offered by different studies, registries, and clinical trials, the use of LVADs is on the rise in high-risk PCIs allowing us to preserve hemodynamic stability during the procedure.
FUNDING
The authors did not declare any sources of funding while this study was being conducted.
CONFLICTS OF INTEREST
None declared.
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Corresponding author: Servicio de Cardiología, Hospital Clínico San Carlos, Profesor Martín Lagos s/n, 28040 Madrid, Spain.
E-mail address: jc.gomezpolo@gmail.com (J.C. Gómez Polo).
Editorials
Transcatheter aortic valve replacement for noncalcified aortic regurgitation. Where are we now?
aServicio de Cardiología, Hospital Clínico Universitario, Valladolid, Spain
bCentro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Original articles
Editorials
Vascular closure devices: the jury is still out
aUnidad de Hemodinámica, Servicio de Cardiología, Hospital General Universitario Dr. Balmis, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain
bDepartamento de Medicina Clínica, Universidad Miguel Hernández, Alicante, Spain
Original articles
Debate
Debate: Asymptomatic severe aortic stenosis: when should we intervene?
The clinician’s perspective
Servicio de Cardiología, Hospital Ramón y Cajal, Madrid, Spain
The interventional cardiologist’s perspective
Unidad de Cardiología Intervencionista, Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo, Vigo, Pontevedra, Spain
