TCT 2019 Revisited

Introduction

By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

At Transcatheter Cardiovascular Therapeutics 2019 (TCT 2019), the annual scientific symposium of the Cardiovascular Research Foundation, we saw many unique trial presentations, but we also saw some presentations that offered additional insight into comprehensive aspects of trials that were presented previously. These have received extensive coverage and will no doubt in many cases be reflected in practice and future guideline updates. Presented here is a selection of trials that continue to evolve and remain "evolutionary" in their impact on practice. Here we have focused on the EXCEL trial, the IVUS-XPL trial, and COAPT trial, with longer outcomes in secondary mitral regurgitation secondary to heart failure. These trials focus on therapeutic strategies of various ages that are nonetheless poised to continue to evolve and increase in patient management.

I thank my colleagues for their insight and trust this will add to our readers' understanding of the changing landscapes of these trials.

EXCEL: Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization

By Barry F. Uretsky, MD, FACC
University of Arkansas Medical Sciences Medical Center
Little Rock, AR

Abdul Hakeem, MD, FACC
Robert Wood Johnson University Hospital
New Brunswick, NJ

ACC.org Trial Summary Excerpt

The goal of the trial was to compare outcomes following coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) with second-generation drug-eluting stents (DES) in patients with unprotected left main disease.

Patients were randomized in a 1:1 fashion to either PCI with Xience everolimus-eluting stents (n = 948) or CABG (n = 957).

The primary outcome, death, stroke, or MI at 3 years for PCI vs. CABG was 15.4% vs. 14.7%, p = 0.018 for noninferiority, p = 0.98 for superiority.

The primary endpoint for PCI vs. CABG was 22.0% vs. 19.2%; odds ratio 1.19 (95% CI 0.95-1.50, p = 0.13). On landmark analysis at 1 year, rates were significantly higher with PCI vs. CABG (15.1% vs. 9.7%, p < 0.001, p for time interaction < 0.001). Higher rates at 5 years with PCI were driven by all-cause mortality (13% vs. 9.9%), and nonprocedural myocardial infarction (6.8% vs. 3.5%). Ischemia-driven target lesion revascularization rates were also higher (16.9% vs. 10%). Stent thrombosis vs. graft occlusion was 1.6% vs. 6.5%. Rates for the primary endpoint were independent of SYNTAX score.1

Expert Commentary

The EXCEL trial is a landmark study in clarifying the role of stenting in the treatment of left main (LM) disease. This trial, comparing LM percutaneous coronary intervention (PCI) with a cobalt-chromium everolimus-eluting stent versus coronary artery bypass grafting (CABG) in 1,905 patients with LM disease and low/intermediate SYNTAX score showed no significant difference between PCI and CABG with respect to the rate of the composite outcome of death, stroke, or myocardial infarction (MI) at 5 years (22% vs. 19.2%; p = 0.13). Patients in the PCI arm had a significantly higher rate of repeat ischemia-driven revascularization (17% vs. 10%; 79% excess risk). Non peri-procedural MI (6.8% vs. 3.5%; 98% excess risk) and all-cause mortality (13% vs. 9.9%; 38% excess risk) were higher with PCI versus CABG. Importantly, although there was no difference in the composite primary endpoint between PCI and CABG at 1 year (hazard ratio 1.05, 0.64-1.71), between 1 and 5 years the survival curves diverged in favor of CABG (61% less risk of composite primary events; absolute risk difference 5.4%). At top level, the main conclusion of the 5-year results seems straightforward, suggesting equivalence between the two revascularization strategies.2 However, the excess risk of individual "hard endpoints," including MI and death, is clear. As such, patients with low-intermediate risk SYNTAX score with significant LM disease must be informed of this difference for truly informed decision-making.

The clinician's conclusion may differ from that of the statistician or clinical trialist. On one hand, the lack of statistical difference between the 2 treatments is reassuring for the use of the less-invasive PCI treatment. On the other hand, the cross-over by 3 years and the continued separation of outcomes favoring CABG at 5 years gives pause to an unabridged endorsement of the less-invasive approach. We agree with the authors that 10-year data will be very helpful in understanding long-term outcome differences. In the meantime, clinicians must incorporate the 5-year data into overall decision-making, which includes the expected life span of the patient in the absence of risk of death from LM disease. Based on the 5-year data from EXCEL, the known robust durability of the internal mammary graft and the higher risk of restenosis with current stents (as shown in the EXCEL trial ), CABG may be the preferred approach in the subset of patients studied in the EXCEL trial who are young and have few comorbidities, whereas a place for PCI may be particularly important in older patients with multiple comorbidities.

A bit of discussion is warranted on the rather contentious issue of including post-procedure MI as an endpoint. One of the reasons the early CABG risk was higher than PCI was a surfeit of post-procedure MI in the CABG group. The question is whether, as an endpoint, post-procedure MI as defined by the Universal Definition, Task Force 3, (present during the EXCEL trial), Task Force 4 (published after the EXCEL trial), or Society for Cardiovascular Angiography and Interventions version really matters at all.3-5 That a patient meets the definition of post-procedure MI, is, in and of itself, of no concern to the patient, or usually to the physician, except when the MI is large. Why was this endpoint included in a study where repeat revascularization as part of the primary endpoint was eliminated because the authors noted that that outcome was "of lesser importance to physicians and patients than death, stroke, and myocardial infarction?"2 We assume that post-procedure MI was included because spontaneous MI is linked to adverse long-term outcomes, related either to sudden death at the time of MI, sudden death due to previous MI and left ventricular dysfunction, death due to left ventricular dysfunction itself, or disability related to heart failure. Even if the authors mount the argument that the definition used in the EXCEL trial for MI most closely reflects long-term prognosis, isn't its inclusion a form of "double counting?" If procedural MI is related to long-term adverse outcomes such as death and subsequent MI, won't these events be captured with long-term follow-up? In our opinion, the decision to include procedural MI unnecessarily confounds interpretation of the EXCEL results.

That being noted, the EXCEL 5-year follow-up is extremely important in informing our decision-making. The results clearly are not black or white, and, like a Rorschach test, different conclusions may be reached by different clinicians. The EXCEL study was carefully performed by excellent investigators. We look forward with great interest to further follow-up.

COAPT: Three-Year Outcomes from a Randomized Trial of Transcatheter Mitral Valve Leaflet Approximation in Patients with Heart Failure and Secondary Mitral Regurgitation

By Mehmet Cilingiroglu, MD, FACC
Bahcesehir University, School of Medicine
Istanbul, Turkey

Ismail Ates, MD, FACC
Bahcesehir University, School of Medicine
Istanbul, Turkey

ACC.org Trial Summary Excerpt

The goal of the trial was to assess the safety and efficacy of transcatheter mitral leaflet approximation using MitraClip among symptomatic heart failure (HF) patients with secondary mitral regurgitation (MR).

Patients with HF and grade 3-4+ MR who remained symptomatic despite maximally tolerated guideline-directed medical therapy (GDMT) were randomized to MitraClip + GDMT (n = 302) vs. GDMT alone (n = 312). This trial had an open-label design.

The primary effectiveness endpoint, HF hospitalization at 24 months for MitraClip + GDMT vs. GDMT, was 35.8% vs. 67.9% (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.40-0.70, p < 0.001). The primary safety endpoint, freedom from device-related complications at 12 months, was 96.6% for MitraClip (p < 0.001).

At 2 years, patients in the GDMT arm could cross over to the MitraClip arm if needed. As a result, total crossover was 18.6% (majority between 2 and 3 years). For the primary results, on ITT, there was still a profound benefit of MitraClip + GDMT over GDMT (annualized rates 35.5% vs. 68.8%, HR 0.49, 95% CI 0.37-0.63, p < 0.001). Benefit of MitraClip on mortality was preserved (42.8% vs. 55.5%, p = 0.001). Among the MitraClip patients, progressive HF requiring LVAD or heart transplant occurred in an additional 3.6% of patients (total 7.4%). Among the patients who crossed over, first HF hospitalization at 1 year was lower (13.8%), and the curves for the other clinical endpoints were more similar to the MitraClip arm than to the GDMT only arm, suggesting that benefit noted for the original MitraClip arm could be replicated in the control arm with MitraClip implantation (crossover).6

Expert Commentary

The COAPT study was a novel and ground-breaking clinical trial in patients with symptomatic functional mitral valve regurgitation with congestive heart failure. Following Food and Drug Administration approval and awaiting favorable Centers for Medicare and Medicaid Services approval, it certainly changed the treatment of patients with congestive heart failure in addition to optimal guideline-directed medical therapy (GDMT). The COAPT 3-year follow-up showed a strong signal that even after a 2-year delay, patients initially randomized to GDMT derive benefit by undergoing mitral valve repair using MitraClip (Abbott; Abbott Park, IL). Not only did curves continue to separate in the intention-to-treat analysis, but crossover patients (only 38% of surviving patients initially randomized to GDMT) also showed major gains, with reduction in hospitalization and mortality and improvement in their quality-of-life measures. What we have seen is that majority of the patients randomized to GDMT did die prior to 2 years.

Some questions remain, such as why eligible patients, still alive, did not end up getting therapy even though MitraClip was offered at no cost to the patients in the study. Most likely, some patients were too sick, but others were feeling well and did not see a reason to crossover. It is also possible that some patients were unaware that this was an opportunity for them, having participated in this trial. We will need to further analyze and understand specific clinical information from those who crossed over versus who did not. It is certainly reassuring see that patients do benefit even after 2 years of optimized GDMT. The number needed to treat was 4.5. It is also important to see that even among patients initially randomized to the MitraClip arm, almost half died by the end of 36 months. So, these patients were very sick. As MitraClip technology clearly works and saves lives, we also have to better understand the clinical criteria for the sickest of the sick patients to properly identify the patients who will truly have survival benefit from this life-saving therapy. On the other hand, patients with symptomatic mitral regurgitation will clearly need to be aggressively treated earlier as opposed to later. Ongoing clinical trials such as RESHAPE-HF (A Randomized Study of the MitraClip Device in Heart Failure Patients With Clinically Significant Functional Mitral Regurgitation) in patients with severely reduced left ventricular ejection fraction and severe symptomatic mitral regurgitation will help us better understand this very sick patient population.

IVUS-XPL: Impact of Intravascular Ultrasound Guidance on Outcomes of Xience Prime Stents in Long Lesions

By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

ACC.org Trial Summary Excerpt

The goal of the trial was to evaluate intravascular ultrasound (IVUS)-guided versus angiography-guided percutaneous coronary intervention (PCI) among patients undergoing drug-eluting stent implantation for long coronary lesions.

Patients undergoing drug-eluting stent implantation for long coronary lesions were randomized to IVUS-guided PCI (n = 700) versus angiography-guided PCI (n = 700). By factorial design, patients were also randomized to 6 months of dual antiplatelet therapy (DAPT) (n = 699) versus 12 months of DAPT (n = 701).

The primary outcome (for IVUS-PCI vs. angio-PCI study) of cardiac death, MI, or target lesion revascularization at 1 year occurred in 2.9% of the IVUS-guided PCI group vs. 5.8% of the angiography-guided PCI group (p = 0.007).

Secondary outcomes for IVUS-PCI vs. angio-PCI study:

  • Cardiac death: 0.4% with IVUS-guided PCI vs. 0.7% with angiography-guided PCIMI: 0% with IVUS-guided PCI vs. 0.1% with angiography-guided PCI
  • Target lesion revascularization: 2.5% with IVUS-guided PCI vs. 5.0% with angiography-guided PCI (p = 0.02)
  • Definite/probable stent thrombosis: 0.3% with IVUS-guided PCI vs. 0.3% with angiography-guided PCI

Five-year outcomes: Cardiac death, MI, or target lesion revascularization at 5 years occurred in 5.6% of the IVUS-guided PCI group vs. 10.7% of the angiography-guided PCI group (p = 0.001). Ischemia-driven revascularization at 5 years occurred in 4.8% of the IVUS-guided PCI group vs. 8.4% of the angiography-guided PCI group (p = 0.007).7

Expert Commentary

The IVUS-XPL trial adds further support for an image-guided approach to coronary stent revascularization. All comparators either trended in favor of intravascular ultrasound (IVUS) guidance in long lesions treated with Xience Prime stents (Abbott; Abbott Park, IL) except for stent thrombosis, which was low and not different between IVUS and angiographic imaging. Most importantly, the primary endpoint of cardiac death, MI, or target lesion revascularization was significantly better at 1-year and 5-year evaluations for the IVUS-guided treatment arm. The benefit at both timeframes represent approximately half as many events for IVUS guidance. These results were predominantly driven by fewer target lesion failures, supported by a parallel reduction in ischemia lesion revascularization.

The results of this trial add to multiple prior trial data showing the benefits of image guidance for PCI, and in this case representing a generally higher risk population. Despite continued evidence for the value of intravascular imaging compared with angiography, its use in the United States remains low. Reasons are complex and include cost, education of operators in use, and time. Unfortunately, interventionalists are so focused on immediate results that the impact of late results is often lost. It's time to move beyond just "getting out of the lab safely" to doing procedures emphasizing optimal late results. Now is the time!

References

  1. Kumbhani DJ. Evaluation of XIENCE versu s Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization - EXCEL (https://www.acc.org). November 7, 2019. Available at https://www.acc.org/latest-in-cardiology/clinical-trials/2016/10/28/19/37/excel. Accessed January 15, 2020.
  2. Stone GW, Kappetein AP, Sabik JF, et al. Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease. N Engl J Med 2019;381:1820-30.
  3. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012;60:1581-98.
  4. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol 2018;72:2231-64.
  5. Moussa ID, Klein LW, Shah B, et al. Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol 2013;62:1563-70.
  6. Bhatt D. Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation - COAPT (https://www.acc.org). September 29, 2019. Available at https://www.acc.org/latest-in-cardiology/clinical-trials/2018/09/21/20/12/coapt. Accessed January 15, 2020.
  7. Bavry AA. Impact of Intravascular Ultrasound Guidance on Outcomes of Xience Prime Stents in Long Lesions - IVUS-XPL (https://www.acc.org). September 29, 2019. Available at https://www.acc.org/latest-in-cardiology/clinical-trials/2015/11/09/15/14/ivus-xpl. Accessed January 15, 2020.

Keywords: Transcatheter Cardiovascular Therapeutics, TCT19, TCT19, Angina, Stable, Atrial Fibrillation, Cardiac Surgical Procedures, Constriction, Pathologic, Coronary Artery Bypass, Coronary Artery Disease, Drug-Eluting Stents, Fractional Flow Reserve, Myocardial, Ischemia, Myocardial Infarction, Myocardial Revascularization, Percutaneous Coronary Intervention, Quality of Life, Stroke, Thrombosis, Ultrasonography, Natriuretic Peptide, Brain, Kidney Failure, Chronic, Myocardial Revascularization, Transcatheter Cardiovascular Therapeutics, Adrenergic beta-Antagonists, Cardiac Surgical Procedures, Cardiomyopathies, Coronary Artery Bypass, Echocardiography, Geriatrics, Heart-Assist Devices, Heart Failure, Heart Transplantation, Heart Valve Diseases, Mitral Valve Insufficiency, Myocardial Infarction, Myocardial Ischemia, Natriuretic Peptide, Brain, Percutaneous Coronary Intervention, Pulmonary Disease, Chronic Obstructive, Stroke, Stroke Volume, Angina Pectoris, Angina, Stable, Angina, Unstable, Angiography, Coronary Restenosis, Drug-Eluting Stents, Myocardial Infarction, Percutaneous Coronary Intervention, Sirolimus, Stents, Thrombosis, Ultrasonography, Interventional


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