Article
Debate
REC Interv Cardiol. 2019;1:51-53
Debate: MitraClip. The heart failure expert perspective
A debate: MitraClip. Perspectiva del experto en insuficiencia cardiaca
aServicio de Cardiología, Hospital Clínico Universitario de Valencia, INCLIVA, Universidad de Valencia, Valencia, Spain bCIBER de Enfermedades Cardiovasculares (CIBERCV), Spain
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Debate: MitraClip. The interventional cardiologist perspective
QUESTION: After the IABP-SHOCK II clinical trial, which would you say is the utility of the intra-aortic balloon pump (IABP)?
ANSWER: In my opinion and yet despite the results of the IABP-SHOCK II,1 the intra-aortic balloon pump (IABP) still plays a significant role in the management of acute myocardial infarction (AMI) and complex percutaneous coronary intervention (PCI) with risks higher than normal.
In high-risk PCIs there is evidence of the benefits derived from using left ventricular assist devices. In the first place, the IABP has shown late benefits in the BCIS-I trial.2 This study randomized patients treated with high-risk PCI—defined as a left ventricular ejection fraction < 30% and > 40% of the lesion related myocardium with intention-to-treat—assessed using scores ≥ 8 in the Jeopardy score. The early study found no significant differences in the primary endpoint at the 28-day follow-up. In the secondary endpoint a numerical difference was found in the mortality rate at the 6-month follow-up, although it was not statistically significant (4.6 in the IABP vs 7.4% in the control group; P = .32) probably due to the low number of patients included (301). However, at the 51-month follow-up,3 the mortality rate was significantly higher in the control group: 38% (12.1/100 patients/year) vs 27.8% (7.9/100 patients/year). The Kaplan-Meier curves showed a significant difference with a hazard ratio of 0.66 (95% confidence interval, 0.44-0.98; P = .039). In our routine clinical practice, patients undergoing high-risk PCI (left main coronary artery with occluded right coronary artery, multivessel disease with depressed left ventricular function) without a technically complex lesion are treated with IABP support.
On the other hand, in the management of AMI there is no doubt that in the presence of mechanical complications like acute mitral regurgitation or interventricular communication, the IABP improves the patient’s condition as long as he is not in a situation of deep cardiogenic shock. This stabilizes the patient until he is in a better condition to undergo definitive surgery.
In the management of AMIs complicated with cardiogenic shock, the role of the IABP would be limited when the shock has already occurred. However, it may be useful for the early management of those stages when the patient is in a high-risk situation and is starting to show hemodynamic impairment (certain degree of hypotension and tachycardia, but no signs of poor target organ perfusion) to achieve an early stabilization. This is so because it is easy to implant in any critical care unit without having to transfer the patient, and thanks to its safety profile confirmed by its low rate of complications.
Q.: In the congress held by the American Heart Association back in 2019 several observational registries showed more adverse events and higher costs compared with the use of the Impella device compared to the IABP. However, these results may be due to the effect of multiple biases. What do you think of all this?
A.: These studies have been published in JAMA and provide different data on the management of patients with post-infarction cardiogenic shock in a retrospective registry.4 This was a very large registry of patients with different baseline characteristics despite the fact that propensity score matching was used. After a thorough reading and analysis of the final outcomes, the mortality rate of the group treated with IABP was clearly lower compared to the one reported by randomized studies on the management of AMI with cardiogenic shock. This is indicative of an early selection bias since it was not a randomized study. However, the group treated with a micro-axial pump had a similar mortality rate compared to the one described by the studies.
We should mention that neither one of the 2 devices showed clinical benefits in this situation compared to standard treatment. This means that the only information provided by that registry is that the least critically ill patients receive an IABP while the most critically ill ones receive a micro-axial flow device. The final outcome shows this early selection bias.
Q.: What is the evidence available on the use of the Impella device in high-risk interventional cardiac procedures? What is the routine clinical practice in your center? And in patients with infarction and cardiogenic shock?
A.: The Impella device has proven useful for the management of high-risk PCIs in the PROTECT II trial.5 This study randomized patients undergoing high-risk PCIs—defined as left main coronary artery disease or last patent vessel disease with an ejection fraction ≤ 35% or 3-vessel disease with an ejection fraction ≤ 30%—eligible to receive an IABP circulatory support device or an Impella 2.5 device. Regarding major cardiovascular events (all-cause mortality, myocardial infarction, stroke or new revascularization), the Impella 2.5 device obtained better results and even showed preventive properties in a multivariate study. If we analyze the study data thoroughly, we can see that its greatest advantage was the lower rate of new revascularizations in part due to the fact that with the Impella device we can treat more complex lesions during the index procedure.
In light of the results from these studies our indications for ventricular support in patients undergoing elective or high-risk PCIs (severe ventricular dysfunction with left main coronary artery disease plus right coronary artery occlusion or 3-vessel disease) are:
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– Technically easy lesion: intra-aortic balloon pump.
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– Technically complex lesion: Impella 2.5 device.
Q.: What escalation of mechanical circulatory support do you recommend in hemodynamically compromised patients or patients with post-infarction cardiogenic shock?
A.: The definition and fast detection of patients who have suffered an AMI is very important. In this sense, the Society for Cardiovascular Angiography and Intervention (SCAI) proposed a new classification of patients after AMI with a series of clinical, analytic, and hemodynamic criteria.6 This classification in stages has proven that there is a clinical correlation with the mortality rates shown by these patients.7 Thus, the stages of hemodynamic impairment can be described as:
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– A (At risk): without hemodynamic impairment.
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– B (Beginning): hypotension and tachycardia, without hypo- perfusion.
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– C (Classic): hypoperfusion without general impairment.
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– D (Deteriorating): hypoperfusion with impairment, non- refractory.
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– E (Extremis): refractory shock.
Currently, there are different types of hemodynamic support with different characteristics regarding the mechanism of action and the effects it has on the heart and coronary circulation.8 Every device offers different hemodynamic support and is associated with a different rate of complications. That is why the risk-benefit ratio should be taken into consideration depending on each patient’s hemodynamic impairment. In my view, the different devices may be indicated for the following stages:
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– Intra-aortic balloon pump: stages A and B.
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– Impella 2.5 device: stage B.
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– Impella CP device, 5.0: stage C.
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– Extracorporeal membrane oxygenation (ECMO): stages D and E.
In general, the degree of support required may be defined in a different way:
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– Coronary support (refractory ischemia): intra-aortic balloon pump.
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– Ventricular support (pulmonary edema): Impella device.
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– Circulatory support (correct hypotension): ECMO.
CONFLICTS OF INTEREST
J. A. Gómez Hospital has received funding from Izasa Hospitals for his collaboration in the implantation of Impella devices and organizing sessions on left ventricular support.
REFERENCES
1. Thiele, H, Zeymer, U, Neumann, et al. IABP-SHOCK II Trial Investigators. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012;367:1287-1296.
2. Perera D, Stables R, Thomas M, et al. Elective Intra-Aortic Balloon Counterpulsation During High-Risk Percutaneous Coronary Intervention. JAMA. 2010;304:867-874.
3. Perera D, Stables R, Clayton T, et al. Long-Term Mortality Data From the Balloon Pump–Assisted Coronary Intervention Study (BCIS-1). A Randomized, Controlled Trial of Elective Balloon Counterpulsation During High-Risk Percutaneous Coronary Intervention. Circulation. 2013;127:207-212.
4. Dhruva SS, Ross JS, Mortazavi BJ, et al. Association of Use of an Intravascular Microaxial Left Ventricular Assist Device vs Intra-aortic Balloon Pump with In-Hospital Mortality and Major Bleeding Among Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock. JAMA. 2020;323:734-745.
5. Dangas GD, Kini AS, Sharma SK, et al. Impact of Hemodynamic Support with Impella 2.5 Versus Intra-Aortic Balloon Pump on Prognostically Important Clinical Outcomes in Patients Undergoing High-Risk Percutaneous Coronary Intervention (from the PROTECT II Randomized Trial). Am J Cardiol. 2014;113:222-228.
6. Baran DA, Grines CL, Bailey S, et al. SCAI Clinical Expert Consensus Statement on the Classification of Cardiogenic Shock:this document was endorsed by the American College of Cardiology (ACC), the American Heart Association (AHA), the Society of Critical Care Medicine (SCCM), and the Society of Thoracic Surgeons in April 2019. Catheter Cardiovasc Interv. 2019;94:29-37.
7. Jentzer JC, van Diepen S, Barsness GW, et al. Cardiogenic Shock Classification to Predict Mortality in the Cardiac Intensive Care Unit. J Am Coll Cardiol. 2019;74:2117-2128.
8. Thiele H, Ohman EM, Desch S, Eitel I, de Waha S. Management of Cardiogenic Shock. Eur Heart J. 2015;36:1223-1230.
QUESTION: Compared to the pressure guidewire what possible advantages does coronary angiography-derived fractional flow reserve (FFRangio) have and what is the current clinical evidence?
ANSWER: Different physiological indices have been developed lately from the 3D reconstruction of the angiogram based on 2 projections and the application of fluid dynamics algorithms. These indices estimate fractional flow reserve (FFR) semi-invasively because, although they are based on percutaneous coronary angiography with contrast, pressure guidewires or drugs are not necessary in the coronary artery.
The most widely studied software package to obtain these indices is the one designed by Medis (QAngio XA 3D, Medis Medical Imaging System, The Netherlands), but there are others in the pipeline.1 The actual software allows us to obtain the baseline quantitative flow ratio (QFR) (fixed QFR [fQFR]). There is another one that adds the speed of the flow of contrast to the estimate (contrast QFR [cQFR]) by quantifying the TIMI frame count. It can also obtain the adenosine-flow QFR (aQFR) with the administration of adenosine and the residual QFR after a hypothetic percutaneous treatment of the lesion.
To this day, the current studies on FFRangio basically focus on analyzing its match (especially that of cQFR) with FFR or the instantaneous wave-free ratio (iFR) obtained using invasive techniques. A study confirmed the modest diagnostic association with the nuclear test,2 but similar to the FFR obtained invasively.
Most of the current evidence shows excellent QFR-FFR matches (> 90%) with the cut-off value of 0.80 with areas under the ROC curve > 0.90.
Two recent meta-analyses reviewed 1721 and 969 vessels studied.3,4 In one of them3 with a 87% match (95% confidence interval [95%CI], 85-89) without any significant differences between the QFR predictive value obtained online and the one estimated at the core lab. The cQFR-iFR match has proven similar to that of the FFR obtained invasively with mismatch classifications of 20%.5
To this day, no follow-up studies or event analyses have reviewed the clinical safety of guiding the intervention with FFRangio compared to FFR.
The theoretical advantages of using FFRangio are:
- It is less invasive. It avoids complications associated with passing the intracoronary guidewire trough the lesion that, though scarce, can still happen.
- It does not require vasodilators. The availability of new non-hyperemic indices does not require the use of drugs with pressure guidewires either.
- Time of assessment is significantly shorter. In the FAVOR II China study, the difference was 4.8 minutes (95%CI, 3.5-6) versus 7 minutes (95%CI, 5.0-10) (P < .001).6 However, this difference of less than 3 minutes is questionable as a practical advantage and should be evaluated in the routine clinical practice.
- Saving costs in intracoronary guidewires and vasodilators; however, no study on costs has been conducted so far and the costs of the software have not been considered either (a “pay per use” model per study conducted after the initial payment plus updates has been suggested). This may require acquiring additional hardware.
- It facilitates the offline functional assessment of non-culprit lesions, thus avoiding new procedures especially of angiographies performed after the infarction acute phase.
Q.: Which do you think are the technical limitations of FFRangio?
A.: FFRangio is nothing but a sophisticated analysis of quantitative angiography. Conceptually, it has the limitation of any functional estimate that uses imaging modalities. In theory, it does not consider factors that may impact the functional repercussion of stenosis or the possible benefit of revascularization such as the size of the irrigated area, the existence of collateral circulation, microvascular damage or myocardial necrosis. Technically, it requires a good angiography which is not always easy to obtain. A posteriori analyses are not always available either. A retrospective study of lesions that performed invasive estimates of FFR (which can be a selection bias of the best angiograms) showed that in 10.3% of the vessels (59 out of 575) the QFR could not be determined due to quality problems in the angiography or in the visualization of the lesion.7
I think the main limitation is the need to use software for measuring purposes. It is well known that the biggest obstacle for the generalization of functional assessments is the interventionist’s trust in his own visual assessment, especially with highly stenotic lesions.8 Outlining the borders of the lesion has a subjective component that, as it happens with visual assessment, can overestimate the lesion and reduce the value of the FFR obtained.
The good results obtained in the studies come from centers experienced in physiology and trained in quantitative angiography and FFRangio. The software provider has designed an education-certification system to learn how to use it. In its current iteration it is still far from being fully automatic, which may be misunderstood after reading the studies published. It is yet to be determined whether the hemodynamic situation, the flow of contrast infused, and the way of acquiring angiographic imaging can alter the value of the QFR obtained.
Q.: Which should be the most appropriate indications for FFRangio with the current state of evidence and which do you think will be its mid-term indications?
A.: I think it is too early to make clinical decisions based on the FFRangio. The match reported in the studies will not necessarily happen in the real clinical practice in all centers, subgroups of patients, and angiograms.
As it occurs with other approaches to FFR, obtaining extreme values may lead to stop using pressure guidewires with matches > 95% (cQFR values < 0.71 or > 0.90),9 although this issue is still under discussion.
In a study of cQFR-invasive FFR match in non-culprit lesions in patients with ST-segment elevation myocardial infarction, a hybrid strategy consisting of using the pressure guidewire only with QFR values between 0.75 and 0.85 would have avoided 58.5% of the pressure guidewires, with a matching classification in 96% of the lesions.10
Patients treated with a primary angioplasty in the acute phase of the infarction could avoid second procedures in the presence of multivessel disease by just assessing the FFRangio.
The HAWKEYE clinical trial11 found that cQFR cut-off values > 0.89 after stent implantation were associated with better prognosis after interventions with drug-eluting stents. In this case the cQFR may be a substitute, in some circumstances, of the optimization of angioplasty with imaging modalities.
Q.: In your opinion, which study or studies would be necessary to bring this technique to the same level as the pressure guidewire? Do you think this will happen anytime soon?
A.: First thing we need is large studies with a large number of patients and centers to show whether it is safe to generalize the decision of revascularizing a lesion or a patient based on the FFRangio. It needs to be confirmed whether the tool actually works. Also, that it does so in most clinical settings, not only in expert hands or clinical trials. To my knowledge, the measures of QFR shown by the studies published so far have been performed by experts, not by interventionists, technicians, or nurses in each case.
Although the visual assessment of angiographic stenoses is the most popular method to decide whether to revascularize or not, there is solid evidence on its important limitations. Although with limitations, establishing functional assessment as the reference method in the clinical practice has improved objectivity and accuracy in the identification of the cases that may benefit the most from revascularization, thus avoiding unnecessary interventions.
The return to quantitative angiography, even if perfected, must ensure that it does not recede on the ground gained due to an increase in randomness in decision making.
As we saw in the case of hyperemic indices, the publication of the results of clinical trials comparing the occurrence of events based on the use of this or that technique and, above all, generalization to other manufacturers of FFRangio can favor its adoption—maybe even full replacement—in the near future.
The FAVOR III Europe-Japan clinical trial (NCT03729739) will randomize 2000 patients with intermediate lesions and stable angina or after revascularization of the infarct related artery to analyze the non-inferiority of guiding revascularization with cQFR values versus FFR values obtained using pressure guidewires.
If FFRangio proves useful and is applicable it should increase the number of physiology-guided revascularizations, and not just through visual assessment. Taking into account the reasons not to use functional assessment,8 this increase should be triggered by a change of mentality in the interventionist and clinician rather than by the greater ease of this technique.
CONFLICTS OF INTEREST
None reported.
REFERENCES
1. Fearon WF, Achenbach S, Engstrom T, et al. Accuracy of Fractional Flow Reserve Derived From Coronary Angiography. Circulation. 2019;139:477-484.
2. Sejr-Hansen M, Westra J, Winther S, et al. Comparison of quantitative flow ratio and fractional flow reserve with myocardial perfusion scintigraphy and cardiovascular magnetic resonance as reference standard. A Dan-NICAD substudy. Int J Cardiovasc Imaging. 2019. https://doi.org/10.1007/s10554-019-01737-z.
3. Westra J, Tu S, Campo G, et al. Diagnostic performance of quantitative flow ratio in prospectively enrolled patients:An individual patient-data meta-analysis. Catheter Cardiovasc Interv. 2019;94:693-701.
4. Zuo W, Yang M, Chen Y, Xie A, Chen L, Ma G. Meta-Analysis of Diagnostic Performance of Instantaneous Wave-Free Ratio versus Quantitative Flow Ratio for Detecting the Functional Significance of Coronary Stenosis. Biomed Res Int. 2019;2019:5828931.
5. Watarai M, Otsuka M, Yazaki K, et al. Applicability of quantitative flow ratio for rapid evaluation of intermediate coronary stenosis:comparison with instantaneous wave-free ratio in clinical practice. Int J Cardiovasc Imaging. 2019;35:1963-1969.
6. Xu B, Tu S, Qiao S, et al. Diagnostic Accuracy of Angiography-Based Quantitative Flow Ratio Measurements for Online Assessment of Coronary Stenosis. J Am Coll Cardiol. 2017;70:3077-3087.
7. Stahli BE, Erbay A, Steiner J, et al. Comparison of resting distal to aortic coronary pressure with angiography-based quantitative flow ratio. Int J Cardiol. 2019;279:12-17.
8. Tebaldi M, Biscaglia S, Fineschi M, et al. Evolving Routine Standards in Invasive Hemodynamic Assessment of Coronary Stenosis:The Nationwide Italian SICI-GISE Cross-Sectional ERIS Study. JACC Cardiovasc Interv. 2018;11:1482-1491.
9. Westra J, Tu S, Winther S, et al. Evaluation of Coronary Artery Stenosis by Quantitative Flow Ratio During Invasive Coronary Angiography:The WIFI II Study (Wire-Free Functional Imaging II). Circ Cardiovasc Imaging. 2018;11:e007107.
10. Lauri F, Macaya F, Mejia-Renteria H, et al. Angiography-derived functional assessment of non-culprit coronary stenoses during primary percutaneous coronary intervention for ST-elevation myocardial infarction. EuroIntervention. 2019;24. pii:EIJ-D-18-01165.
11. Biscaglia S, Tebaldi M, Brugaletta S, et al. Prognostic Value of QFR Measured Immediately After Successful Stent Implantation:The International Multicenter Prospective HAWKEYE Study. JACC Cardiovasc Interv. 2019;12:2079-2088.
QUESTION: Compared to the pressure guidewire what possible advantages does coronary angiography-derived fractional flow reserve (FFRangio) have and what is the current clinical evidence?
ANSWER: Guidewire pressure-derived fractional flow reserve (FFR) is the most highly validated physiological index for the analysis of coronary stenoses.1,2 Despite the large scientific evidence supporting its prognostic impact on the assessment of patients with coronary artery disease and great cost-effective ratio, its use, though on the rise, is still not very popular.3 And this is so even despite the fact that only one third of the intermediate angiographic lesions considered significant through visual assessment are eventually confirmed as significant at the physiological analysis.4,5 The main reasons are that performing the FFR requires advancing a guidewire—which is not the best thing to do from the standpoint of maneuverability—through a coronary artery that has some degree of atheromatous disease. Also, to assess hyperemia, it requires the administration of drugs that can have undesirable effects effects.6
In order to solve these issues, easier non-hyperemic indices such as the instantaneous wave-free ratio (iFR), the diastolic pressure ratio (dPR), and the resting full-cycle ratio (RFR)7 have been developed. They all avoid using drugs, but require the advancement of an intracoronary guidewire. FFRangio can be performed using different software, such as the quantitative flow ratio (QFR; Medis, The Netherlands) and others in the pipeline like the 3D-CA (HeartFlow, United States) which provides the same information only with the angiography without having to advance the guidewire or use drugs, which is precisely their main advantage. Similarly, there are different software available to perform this analysis using computed tomography that have already generated evidence;8 they are based on 3D reconstruction and computational fluid dynamics.9 They have proved to match the FFR adequately in different contexts10,11 with a cut-off value of 0.80, an apparently higher accuracy of iFR,12,13 and an adequate intra- and inter-observer reproducibility in centralized analyses.14
The FAVOR pilot study,15 that gained the CE marking for the QFR software back in 2017, recruited 88 patients with stable coronary artery disease and non-ostial lesions, and proved the good correlation between the QFR and the FFR. Also, it proved that the values of FFRangio in situations of hyperemia (with adenosine [aQFR]) did not increase diagnostic accuracy compared to measurements without hyperemia (only with the administration of contrast [cQFR]), which means that the use of drugs can be avoided. These results have also been confirmed in a recent meta-analysis conducted by Westra et al.16 that only included prospective registries. It showed he high negative predictive value of FFRangio that would avoid unnecessary delayed procedures.
Q.: Which do you think are the technical limitations of FFRangio?
A.: One in 5 vessels cannot be analyzed accurately with the FFRangio when the study is performed retrospectively, that is, without an optimal angiography based on easy recommendations including 2 projections of the vessel under study with, at least, a 25º difference and a recording at 15 images per second. When performed this way, images can be analyzed more precisely in up to 90% of the vessels. However, the software available is still limited with ostial or bifurcation lesions. Other than the aforementioned, the factor that often slows down a correct analysis is the crossing of vessels in the studied lesion, which explains why when the images are specifically acquired, the possibility of performing the analysis is much higher. As a matter of fact, integrating this type of software online in the catheterization laboratory is essential to obtain FFRangio values and angiographic acquisition simultaneously and correct the latter when inadequate. This is so because with offline analyses the quality of angiography cannot be changed. Another factor that can be misleading and should be taken into consideration is that, although the contour of the vessel is acquired automatically, manual corrections can still be made. To minimize the impact of this subjective factor operators need to have proper training and certification in this technique. Finally, although evidence is scarce on this regard, we should ask ourselves to what extent variations in microcirculation that affect coronary flow (like in the infarct related artery or in stable patients with significant microvascular abnormalities) can also impact the results of the FFRangio analysis. In return, this software asseses the entire length of the vessel, not only individual lesions, to decide what part of the vessel should be treated in cases of tandem lesions to be more precise and effective therapeutically speaking (QIMERA-1, NCT04200469).
Q.: Which should be the most appropriate indications for FFRangio with the current state of evidence and which do you think will be its mid-term indications?
A.: From my own perspective, one of the most practical, efficient, and cost-effective uses will be to assess non-culprit lesions in the myocardial infarction setting.14,17 Although, as I mentioned at the beginning, complete revascularization with pressure guidewire has proven useful in this context, the truth is that when dealing with culprit artery revascularizations the clinical context is often that of an emergency. Therefore, no treatment is administered or physiological assessment of the lesions performed in the remaining vessels. This leads to a second procedure with the resulting risks and costs that, in many cases, can be avoided since FFRangio assessments rules out significance in over 50% of the lesions. Actually, when a second procedure is performed, the most common finding is that, according to the FFR angio, the severity of the stenoses observed in non-culprit arteries often improves compared to the acute phase. As a matter of fact, the QIMERA pilot study14 confirmed that in patients with cQFR values < 0.82 in non-culprit arteries during the first procedure, the delayed procedure could be avoided without assuming any risks.14
Q.: In your opinion, which study or studies would be necessary to bring this technique to the same level as the pressure guidewire? Do you think this will happen anytime soon?
A.: We will probably need several prospective and controlled studies that compare both tools in different clinical settings: infarctions, stable patients, pre- and post-angioplasties, etc. In this sense, our group simply conducted a prospective comparison among different non-hyperemic tools (RFR and QFR versus FFR)—to be published shortly—proving that there is a better correlation between QFR and FFR. Therefore, these strategies that do not require advancing a coronary guidewire for physiological assessment will probably be widely used. However, other technological achievements still need to be made first.
On the other hand, I don’t believe one technique will end up replacing the other in the mid-term. Actually, evidence suggests that a combination of both can be very useful. Thus, with QFR values < 0.75 or > 0.85 it would not make sense to run more physiological tests (avoiding 60% of pressure guidewires). Regarding the gray values in that area a guidewire-based non- hyperemic index may be used, which could reach sensitivity and specificity values of 97%, both consistent with an analysis conducted by our group of over 100 lesions with a 94.5% positive predictive value and a 98.5% negative predictive value. This combined approach would avoid the administration of adenosine to 100% of the patients and minimize the need to advance an intracoronary guidewire. According to the interventional cardiologists surveyed, this is the main setback for the physiological assessment of lesions.18
CONFLICTS OF INTEREST
The center received unconditional research funding from Medis (The Netherlands).
REFERENCES
1. Zimmermann FM, Ferrara A, Johnson NP, et al. Deferral vs. performance of percutaneous coronary intervention of functionally nonsignificant coronary stenosis:15-year follow-up of the DEFER trial. Eur Heart J. 2015;36: 3182-3188.
2. Xaplanteris P, Fournier S, Pijls NHJ, et al. Five-Year Outcomes with PCI Guided by Fractional Flow Reserve. N Engl J Med 2018;379:250-259.
3. Götberg M, Cook CM, Sen S, Nijjer S, Escaned J, Davies JE. The Evolving Future of Instantaneous Wave-Free Ratio and Fractional Flow Reserve. J Am Coll Cardiol. 2017;70:1379-402.
4. Lindstaedt M, Spiecker M, Perings C, et al. How good are experienced interventional cardiologists at predicting the functional significance of intermediate or equivocal left main coronary artery stenoses?Int J Cardiol. 2007;120:254-261.
5. Tonino PAL, De Bruyne B, Pijls NHJ, et al. Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention. N Engl J Med. 2009;360:213-224.
6. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med. 1996;334:1703-1708.
7. Sen S, Escaned J, Malik IS, et al. Development and Validation of a New Adenosine-Independent Index of Stenosis Severity From Coronary Wave–Intensity Analysis. J Am Coll Cardiol. 2012;59:1392-1402.
8. Min JK, Leipsic J, Pencina MJ, et al. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. JAMA. 2012;308:1237-1245.
9. Morris PD, Narracott A, von Tengg-Kobligk H, et al. Computational fluid dynamics modelling in cardiovascular medicine. Heart. 2016;102:18-28.
10. Tu S, Barbato E, Köszegi Z, et al. Fractional Flow Reserve Calculation From 3-Dimensional Quantitative Coronary Angiography and TIMI Frame Count. JACC Cardiovasc Interv. 2014;7:768-777.
11. Tu S, Lansky A, Barbato E, et al. Diagnostic Accuracy of Fast Computational Approaches to Derive Fractional Flow Reserve From Diagnostic Coronary Angiography. JACC Cardiovasc Interv. 2016;9:2024-2035.
12. Emori H, Kubo T, Kameyama T, et al. Quantitative flow ratio and instantaneous wave-free ratio for the assessment of the functional severity of intermediate coronary artery stenosis. Coron Artery Dis. 2018;29:611-617.
13. Asano T, Katagiri Y, Chang CC, et al. Angiography-Derived Fractional Flow Reserve in the SYNTAX II Trial:Feasibility, Diagnostic Performance of Quantitative Flow Ratio, and Clinical Prognostic Value of Functional SYNTAX Score Derived From Quantitative Flow Ratio in Patients With 3-Vessel Disease. JACC Cardiovasc Interv. 2019;12:259-270.
14. Cortés C, Rodríguez-Gabella T, Gutiérrez H, et al. Quantitative Flow Ratio en infarto de miocardio para la evaluación de lesiones en arterias no culpables:estudio piloto QIMERA. REC Interv Cardiol. 2019;1:13-20.
15. Tu S, Westra J, Yang J, et al. Diagnostic Accuracy of Fast Computational Approaches to Derive Fractional Flow Reserve From Diagnostic Coronary Angiography. JACC Cardiovasc Interv. 2016;9:2024-2035.
16. Westra J, Tu S, Campo G, et al. Diagnostic performance of quantitative flow ratio in prospectively enrolled patients:An individual patient?data meta?analysis. Catheter Cardiovasc Interv. 2019;94:693-701.
17. Sejr-Hansen M, Westra J, Thim T, et al. Quantitative flow ratio for immediate assessment of nonculprit lesions in patients with ST-segment elevation myocardial infarction-An iSTEMI substudy. Catheter Cardiovasc Interv. 2019;94:686-692.
18. Tebaldi M, Biscaglia S, Fineschi M, et al. Evolving Routine Standards in Invasive Hemodynamic Assessment of Coronary Stenosis. JACC Cardiovasc Interv. 2018;11:1482-1491.
QUESTION: What would you say is the current state of the evidence available on the closure of patent foramen ovale (PFO)?
ANSWER: The closure of PFO to prevent embolic events has been a matter of discussion for cardiologists and neurologists in the therapeutic decision-making process for years. The main reason was the lack of randomized clinical trials showing the efficacy (or inefficacy) of performing this percutaneous procedure in certain patients diagnosed with cryptogenic stroke. After the publication of 3 randomized clinical trials in 2017 in one of the highest-impact medical journals and posterior meta-analysis, the results suggest long-term clinical benefits in patients with certain anatomical, echocardiographic, and clinical characteristics who have suffered a stroke (or neurological event of embolic profile) without apparent reason.1
Thus, today, heart teams led by neurologists specialized in cerebrovascular disease and interventional cardiologists should assess together the eligibility of these patients. According to studies recently published, certain criteria that can be established individually are predictors of benefits from the percutaneous closure of PFO: age < 60 years old; presence of interatrial septal aneurysm; acute right-to-left shunt; presence of redundant Eustachian valve or Chiari network in the right atrium; and even a length of the PFO tunnel > 10 mm.
Unlike the favorable evidence available on the reduction of long-term embolic events, there is concern on the growing number of atrial fibrillation (AF) events consistently observed in populations treated with devices for the closure of PFO. There may be 2 reasons for this: the existence of a misdiagnosed arrhythmogenic substrate in the form of paroxysmal AF that may be causing the embolic event or the direct correlation between AF and the intracardiac device implantation since many FAs are detected postoperatively within the first few weeks. The need to detect more effectively the presence of FA events in patients with cryptogenic stroke has increased the use of prolonged electrocardiogram tests in the form of prolonged Holter monitoring or subcutaneous Holter to register heart rhythm.
Q.: Why do you think it has taken so many years since the first trial was conducted to show the benefits of the closure of PFO? What is the difference between the first studies that were not positive and the latest ones that are?
A.: In my opinion, there are a number of reasons that can justify the lack of scientific evidence until recently. First, the development of safer and more effective devices, since the first trials were conducted with less optimal devices that are no longer in use. Second, the experience of interventional cardiologists in the management of structural heart disease has grown exponentially over the last 10 years with the development of units specialized in non-coronary procedures. Third, rigor in the study design and conduction and in the selection of patients eligible from the clinical and imaging modality standpoints (bubble echocardiogram; transesophageal echocardiograph; transcranial Doppler ultrasound; magnetic resonance imaging) has improved diagnosis and contributed to plan proper therapeutic strategies. Finally, the recruitment rate of the first clinical trials was very slow, indicative of reluctance from patients and doctors to participate in these trials.
Q.: From the clinical perspective and imaging modality standpoint, what patients are good candidates to benefit from the closure of PFO?
A.: Clinical trials have been recruiting patients < 60 in a similar way thinking that, at that age, the appearance of embolic events may be justified for other reasons (arterial hypertension, diabetes mellitus, hypercholesterolemia, subclinical atheromatous disease, active smoking).
The importance of imaging modalities, in particular echocardiography, has consolidated steadily. On the one hand, transthoracic bubble echocardiogram with bubble study (agitated saline solution) can identify the presence of an interatrial septal shunt and determine the severity of right-to-left shunt. Also, the transcranial Doppler ultrasound can quantify the right-to-left shunt considered serious in the presence of shower and curtain pattern. An acute, at least moderate, shunt has been identified as a predictor of greater benefit following the closure of PFO.
The transesophageal echocardiogram prior to the procedure is highly recommended. It discards abnormalities not found on the transthoracic echocardiogram like the presence of other septal defects (multiperforated septa) or even interatrial communication and identifies the presence of interatrial septal aneurysm, Chiari network or redundant Eustachian valve. Several studies identify the aneurysm as a predictor of embolic recurrences2; also, it can complicate the procedure when deciding the size and shape of the device that will be used.
Recently, the importance of a large Chiari network and a redundant Eustachian valve has been reported. The implication here is trying to divert blood flow from the inferior cava vein towards the septum in order to favor the passing of thrombi through the PFO.
The length of the PFO tunnel and its degree of separation—clearly visible on the transesophageal echocardiography and important to plan the procedure—has not been studied very much. However, it may be associated with greater benefits from the closure of PFO when the separation is wide (> 4 mm) and the tunnel is long (> 10 mm).2
Q.: Are there relevant differences among different devices?
A.: There are several specific devices available for the closure of PFO. To make things easier we can distinguish between 2 different types: double-disc devices (most of them) and devices with different designs. Design is important for several reasons: in the first place because it must seal the shunt completely; secondly, it must be safe enough to not cause any associated problems like the formation of thrombi on the device or the erosion or perforation of interatrial septum or adjacent structures (atria, aorta) that would lead to potentially serious complications. On the other hand, the impact that the implantation of an intracardiac foreign body has on the appearance of atrial tachyarrhythmias (in particular, AF) should be minimal because it can condition antithrombotic therapy after the implant or promote the appearance of embolic events. And lastly, the highly rare (but still worthy of being taken into consideration) possibility that the patient is allergic to some of the metals these devices are made out of, especially nickle.
Double-disc devices are very similar to one another, they have been around for quite a while (they are the most widely used devices of all), there is a wide range of measures, and they are highly effective for the complete closure of PFO. Regarding other designs, maybe the most original of all is the one that allows direct suture of PFO and anchoring of minimal residual material to interatrial septum. Its pitfall is the greater complexity of the procedure and little experience of the results especially in the long-run.
Actually, the objective is to achieve the complete closure of the shunt through the septum without side effects or immediate or long-term complications associated with the device or the most widely used technique, either one of the two.
Q.: Which should be the next trial in this setting?
A.: We have learned from previous trials how difficult it is to randomize patients with this condition due to the reluctancy of patients and doctors.
Now, after seeing all the evidence available in the medical literature, it does not seem logical to repeat similar trials to compare drugs and devices. It is not easy to come up with an original design in this setting because the low rate of events requires longer follow-ups. In my opinion, comparing devices to one another does not make too much clinical sense here. An option would be to reconsider the possible efficacy of the closure of PFO in patients with migraines and right-to-left shunt. Using specific and selected criteria; proper neurologist-cardiologist coordination; follow-up images; biomarkers; and quality of life surveys, patients eligible to undergo the percutaneous closure of PFO vs targeted medical therapy could be randomized. Also, the efficacy and safety endpoints could be assessed in both groups.
CONFLICTS OF INTEREST
F. Hernández Hernández is a proctor of percutaneous closure of patent foramen ovale for Abbott, Izasa, Cathmedical Cardiovascular and SMT.
REFERENCES
1. Ahmad Y, Howard JP, Arnold A, et al. Patent foramen ovale closure vs. medical therapy for cryptogenic stroke:a meta-analysis of randomized controlled trials. Eur Heart J. 2018;39:1638-1649.
2. Nakayama R, Takaya Y, Akagi T, et al. Identification of High-Risk Patent Foramen Ovale Associated With Cryptogenic Stroke:Development of a Scoring System. J Am Soc Echocardiogr. 2019;32:811-816.
QUESTION: What would you say is the current state of the evidence on the closure of the patent foramen ovale (PFO)?
ANSWER: Recent randomized clinical trials show greater benefits with the closure of the PFO compared to the medical therapy in patients with PFO-related cryptogenic stroke (CS).1-4 Despite a 64% risk reduction this benefit is only applicable to “high-risk patients” and requires a high number needed to treat (130 patients).5 Also, there are several gaps that prevent the generalization of its therapeutic indication and required individual indications for every patient.
In spite of everything, to this day there is enough body of knowledge for the reasoned indication of medical therapy or the percutaneous closure of the PFO in patients with PFO-related CS. In this context, the European take on this issue may help. A document signed by 8 scientific societies including the European Association of Percutaneous Cardiovascular Interventions (EAPCI), the European Heart Rhythm Association (EHRA), the European Association for Cardiovascular Imaging (EACVI), and the European Stroke Organisation (ESO).6
The arrival of a new technology or therapy is often like a rollercoaster and the closure of the PFO is not an exception. New discoveries and therapies are followed by unjustified euphoria based on intuition, which eventually leads to overuse. Also, there is no real evidence of its effectiveness followed by a significant risk for iatrogenic disease and, at best, a considerable futile investment. This is precisely what happened during the years when observational and cohort studies were conducted (from 1995 to 2011 approximately). Years of “disbelieve and denial” followed the appearance of the first results of clinical trials, all of which were negative.7-9 The generalized refusal of the percutaneous closure of the PFO that followed these studies (from 2012 through 2018) was not justified either as the positive results of 4 clinical trials recently published show.1-4
Q.: Why do you think it has taken so many years since the first trial was conducted to show the benefits of the closure of the PFO? What is the difference between the first studies that were not positive and the latest ones that are?
A.: The problem with PFO-related CS is that it is not a very aggressive type of stroke with 2 key aspects that make it difficult to obtain solid results in the studies conducted:
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- The PFO is very prevalent in healthy populations where it is not a relevant risk factor, which is a significant confounding factor.
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- In patients with PFO-related CS, the risk of recurrence is low (annual 0.20% to 1.27%),5,6 and both the traditional antiplatelet therapy and the percutaneous closure are effective.
The mere fact of showing traditional vascular risk factors like smoking, hypertension, diabetes or old age involves a higher risk of an early stroke and a higher risk of recurrence compared to the presence of PFO. This adds extra difficulty to the routine clinical practice since traditional vascular risk factors coexist with the presence of PFO.
The main problem here is to identify the subgroup of patients in whom the PFO is the direct cause for the stroke. Also, if the study design is assessing the effectiveness of a therapy regarding the risk of recurrence—since it is low—it requires, at best, a large sample and long follow-up. As an added difficulty, preemptive therapy with antiplatelet drugs is effective for the prevention of stroke recurrences in this context. Also, all clinical studies should be compared to this control group since it is already receiving effective treatment.
These aspects can be easily seen in 1 of the 3 negative studies published in 2012 (RESPECT),8 which becomes 1 of the 4 positive studies after the 9-year follow-up of the original population who participated in the clinical trial was published back in 2017.3
Q.: From the clinical perspective and imaging modality standpoint, what patients are good candidates to benefit from the closure of the PFO?
A: The presence of septal aneurysm or the detection of moderate-acute shunt have been strongly associated with the PFO as the cause for the CS both in clinical and observational studies6,7 and with the benefits of closure compared to medical therapy.
The therapeutic decision and, in particular, the option to perform the closure of the PFO in patients who have suffered from a CS should be based on how we answer to these 2 questions:
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- What are the chances that the PFO identified in the patient is the cause for the stroke and not just an innocent witness?
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- If the PFO is the probable cause for the stroke, what is the risk of recurrence?
The most relevant utility factors to confirm the probability that the PFO is the direct cause for the CS are:
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- Septal aneurysm.
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- Moderate-acute right-to-left shunt (corresponding to the shower and curtain patterns on the transcranial Doppler ultrasound).
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- Presence of deep vein thrombosis.
Other less relevant factors identified given the lack of prospective studies are:
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- The presence of Eustachian valve, Chiari network or PFO extensive channel.
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- Clinical aspects indicative of paradoxical embolism: consistent with the Valsalva maneuver, prolonged immobilization, tourist class syndrome, thrombophilic status, etc.
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- Age < 55 years old.
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Score obtained in the RoPE grading system10 as an additional tool in this evaluation and in association with previous parameters.
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- Lack of traditional cardiovascular risk factors.
No neuroimaging patterns have been identified consistently associated with the causal role played by the PFO in the development of CS.
Regarding the assessment of the risk of recurrence, no variable per se facilitates any quantitative predictions.
The high-risk patients of clinical trials should be candidates for the closure of the PFO because they are the subgroup in which the analysis of results shows clinical and statistically significant differences (relative risk, 0.27; 95% confidence interval [95%CI], 0.11-0.70).5
Old age does not exclude a causal PFO-related CS. As a matter of fact, a similar risk has been reported in young patients. However, to this day we should not consider the percutaneous closure of the PFO given the relatively low risk of recurrence, the profile of patients in the clinical trials (18-60 years old), and the long-term benefit shown with an unfavorable cost-effectiveness ratio for the percutaneous closure in this age group.
To indicate the closure of the PFO these factors are especially important:
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- Interatrial septal aneurysm (odds ratio [OR], 3.0; 95%CI, 1.8-4.8).
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- PFO of a large size or right-to-left shunt (OR, 3.0; 95%CI, 1.9-4.6).
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- In particular, the association between interatrial septal aneurysm and acute shunt.
Other factors identified that should be taken into account are:
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- Thrombophilic status (OR, 2.75; 95%CI: 1.17-6.49).
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- Previous treatment with acetylsalicylic acid vs oral anticoagulants (OR, 2.5; 95%CI, 1.1-6.1).
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- Infarction vs transient ischemic attack as clinical presentation including infarction seen on neuroimages (OR, 3.0; 95%CI, 1.4-6.5).
Q.: What is the best medical therapy after the closure of the PFO?
A.: There is significant controversy among the different guidelines and there are no solid pieces of evidence. Considering that the endothelization process can extend for up to 5 years after the implantation,6 that clinical trials kept antiplatelet therapy for, at least, 2 years (5 years in 2 of them), and the overall behavior of ischemic stroke and, in particular, CS the pattern should be: keep dual antiplatelet therapy for a month and continue with single antiplatelet therapy (acetylsalicylic acid, 100 mg/day) for, at least, 2 years (5 years if we follow the European recommendation).
At 5 years, before withdrawing antiplatelet therapy, the patient should be assessed by a stroke expert to decide on the withdrawal of the treatment based on the patient’s clinical profile (age, coexisting factors of vascular risk, PFO total occlusion or residual shunt, life habits, tolerance to treatment, etc.).
Q.: Which should be the next trial in this setting?
A.: These are some of the aspects that are still under discussion and should be taken into consideration in future trials:
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- Better identification of the profile of high-risk patients including the analysis of additional or current risk factors (older age, severity of shunt in baseline conditions, size of interatrial septal aneurysm, presence of Chiari network or Eustachian valve, etc.).
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- Conduct adequately designed clinical trials to see the potential benefits of direct-acting oral anticoagulants compared to the percutaneous closure of the PFO.
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- Obtain long-term follow-up information since the potential benefit of the closure of the PFO is cumulative over time and the long-term risk of medical therapy is not very well known.
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- Assess not only the risk of recurrence, but also quality of life including the degree of disability in basic activities of daily living after recurrence (eg, routine use of the Rankin modified scale in acute stroke studies).
Additionally, observational prospective registries should be conducted in the clinical practice.
In conclusion, to this day we have enough scientific evidence to conclude that the closure of the PFO is superior to antithrombotic therapy regarding the risk of recurrence in patients with PFO-related CS. Patients with interatrial septal aneurysm or massive shunt could benefit the most from this intervention. Future studies should analyze the closure of the PFO in patients not included in the trials like patients > 60 years and patients with other associated cardiovascular risk factors.
CONFLICTS OF INTEREST
None reported.
REFERENCES
1. Søndergaard L, Kasner SE, Rhodes JF, et al. Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med. 2017;377:1033-1042.
2. Mas JL, Derumeaux G, Guillon B, et al.;CLOSE Investigators. Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke. N Engl J Med. 2017;377:1011-1021.
3. Saver JL, Carroll JD, Thaler DE, et al.;for the RESPECT Investigators. Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke. N Engl J Med. 2017;377:1022-1032.
4. Lee PH, Song JK, Kim JS, et al. Cryptogenic Stroke and High-Risk Patent Foramen Ovale:The DEFENSE-PFO Trial. J Am Coll Cardiol. 2018;71:2335-2342.
5. Turc G, Calvet D, Guérin P, et al.;CLOSE Investigators. Closure, Anticoagulation, or Antiplatelet Therapy for Cryptogenic Stroke With Patent Foramen Ovale:Systematic Review of Randomized Trials, Sequential Meta?Analysis, and New Insights From the CLOSE Study. J Am Heart Assoc. 2018;7:e008356.
6. Pristipino C, Sievert H, D'Ascenzo F, et al. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. Eur Heart J. 2019;40:3182-3195.
7. Furlan AJ, Reisman M, Massaro J, et al.;CLOSURE I Investigators. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366:991-999.
8. Carroll JD, SaverJL, Thaler DE, et al.;RESPECT Investigators. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013;368:1092-1100.
9. Meier B, Kalesan B, Mattle HP, et al.;PC Trial Investigators. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368:1083-1091.
10. Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology. 2013;81:619-625.
Original articles
Review Articles
Original articles
Editorials
Ventricular pressure-volume loop and other heart function metrics can elucidate etiology of failure of TAVI and interventions
aDepartment of Mechanical Engineering, McMaster University, Hamilton, Ontario, Canada
bSchool of Biomedical Engineering, McMaster University, Hamilton, Ontario, Canada
Special articles
Role of computed tomography in transcatheter coronary and structural heart disease interventions
aServicio de Cardiología, Hospital Universitario Álvaro Cunqueiro, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Pontevedra, Spain
bServicio de Cardiología, Hospital de la Santa Creu i Sant Pau, Instituto de Investigación Biomédica Sant Pau (IBB Sant Pau), Barcelona, Spain
cServicio de Cardiología, Complejo Asistencial Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
dCentro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Debate
“Orbiting” around the management of stable angina
The interventional cardiologist’s perspective
aServicio de Cardiología, Complejo Asistencial Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
bCentro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
The clinician’s perspective
aInstituto Cardiovascular, Hospital Clínico San Carlos, Madrid, Spain
bDepartamento de Medicina, Facultad de Medicina, Universidad Complutense, Madrid, Spain