Important Interventional Trials From SCAI 2020
The Society for Cardiovascular Angiography and Interventions 2020 Scientific Sessions Virtual Conference (SCAI 2020) included a number of unique studies of importance to the interventionalist. Summaries of and comments about those studies are presented here, including important sub-studies from two large multicenter trials: ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) and REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial).
To aide readers in targeting the summaries of interest and to get quick updates, we have added Quick Takes from each commentary. I trust these will be useful to identify trials of interest and provide a "memory snapshot" of the authors' main points.
As always, comments are appreciated.
ISCHEMIA Intermediate LM Sub-Study
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
- Intermediate (25-49%) left main (LM) disease is associated with greater baseline coronary artery disease and greater risk of a composite of adverse clinical events, which is unaffected by an invasive or conservative management strategy.
- Significant quality of life benefits with regard to angina can be achieved with an invasive strategy.
The now classic coronary artery bypass grafting surgery (CABG) versus medical treatment studies showed the prognostic survival benefit for LM revascularation. However, assessment of LM severity and long-term outcomes for lesser degrees of stenosis are not well categorized. The VA-CABG (Veterans Affairs Coronary Artery Bypass Surgery Cooperative Study Group) of CABG versus medical management suggested that the benefits of revascularization were greater for the more severe (LM >75%) lesions compared to LM 50-75%. However, the impact of lesser degrees of LM stenosis has not been well assessed.
The ISCHEMIA trial investigated outcomes for patients with moderate or severe ischemia randomly assigned to an invasive plus optimal medical strategy versus an optimal medical only strategy. Patients with LM ≥50% on coronary computed tomography angiography screening were excluded from randomization. There were 962 patients in the intermediate LM group and 3 times as many patients (2,737) in the <25% LM group. Thus, the LM sub-study provided an opportunity to assess the outcomes for intermediate LM disease defined as 25-49% compared to LM disease <25%.
Baseline and outcome findings demonstrated the following for patients with intermediate LM disease (compared to LM disease <25%):
- Greater extent of total coronary artery disease (more 2- and 3-vessel disease and higher SYNTAX scores)
- A worse prognosis with more frequent cardiovascular events (primary endpoint = time to cardiovascular death, myocardial infarction [MI], hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest); adjusted hazard ratio 1.31; 95% confidence interval, 1.06, 161; p < 0.0123
- No difference between invasive and conservative treatment strategies for primary or major secondary clinical outcomes
- As in the main ISCHEMIA results, an increase in procedural MI but a decrease in non-procedural MI with invasive strategy
- A similar quality of life, including angina-specific parameters (equivalent Seattle Angina Questionnaire 7 Summary and Angina Frequency scores for both groups)
- As in the main ISCHEMIA results, significant and durable benefit in the invasive group for improving angina-related quality of life in symptomatic patients
These results are important because they emphasize the potential importance of intermediate LM disease based on coronary computed tomography angiography assessment representing overall more coronary artery disease and a potential for symptomatic benefit for the intermediate group with revascularization. The issue of potential reductions in future MI is important but will need longer follow-up to assess for a potential late benefit of revascularization. The persistent, unreported finding in ISCHEMIA trial and sub-study results is the lack of information on the extent to which operators achieved complete revascularization and to what extent complete, "surgical-like" revascularization affected outcomes.
Telemedicine and the LATIN Study
By Tanveer Rab, MD, FACC
Emory University School of Medicine
- Telemedicine offers a cost-effective method of creating massive population-based ST-segment elevation myocardial infarction (STEMI) systems of care that utilize local synergies to overcome vast infrastructure deficits.
- LATIN (Latin American Telemedicine Infarct Network) telemedicine provides a global template for heart attack management in developing regions of Africa, the Middle East, and Southeast Asia.
Long overdue, telemedicine has taken a front seat in the current coronavirus disease 2019 (COVID-19) pandemic and is here to stay. The effectiveness of this technology in screening large numbers of patients with STEMI in remote areas of South America was presented by Dr. Sameer Mehta at the SCAI 2020 virtual meeting.
Between 2013 and 2019, LATIN covered an area populated by 100 million people in remote areas of Argentina, Brazil, Colombia, and Mexico. The network included a hub-and-spoke model; 780,234 patients were screened in 313 centers or "spokes" in remote locations. Patients were triaged by electrocardiographic analysis by telemedicine experts, and 1.1 % were diagnosed with STEMI. Of the diagnosed patients, 46.1% were transferred to one of 47 "hubs," and of these, 78% underwent reperfusion therapy with percutaneous coronary intervention (PCI). Time to telemedicine diagnosis was 3.5 minutes, mean door-to-balloon time was 48 minutes, and the STEMI mortality rate was 5.2%.
In these economically disadvantaged populations targeted by LATIN, inappropriate STEMI care and transfers were substantially reduced, with economic savings of $119 million. Small networks in the United States are exploring this model, and much will be gained from implementing this strategy in the United States by reducing costs related to inappropriate STEMI activation. As an extension of LATIN, further advancement of this telemedicine technology includes a stroke network and artificial intelligence-enabled smartphone technology to detect STEMI through a single lead and telemedicine network activation.
The OMEF Study
By Arnold Seto, MD, MPA
University of California, Irvine School of Medicine
- Adjunctive imaging modalities such as optical coherence tomography (OCT) can improve the assessment of angiographically intermediate coronary lesions.
- Specific cut-offs of minimal lumen area (MLA) and % area stenosis derived by OCT potentially discriminate angiographically intermediate coronary lesions with a positive fractional flow reserve (FFR) (<0.80) from those with a negative FFR (≥0.80).
This trial examined the best cut-off values of OCT MLA and area stenosis to correlate with FFR <0.80. Dr. Rocco Vergallo and colleagues from Gemelli Medical Center in Rome, Italy, presented the OMEF (Optical Coherence Tomography Measures Predicting Fractional Flow Reserve) study. Their goal was to utilize the impeccable anatomic detail of OCT in predicting FFR using pooled patient level data collected from different studies that collected both FFR and OCT data. They had an overall population of 489 patients, of which 89% had stable angina. They found that the correlation R value between FFR and OCT MLA was relatively modest at 0.525 and that OCT area stenosis was similarly modestly predictive with R = 0.482. The presence of ulceration and thrombus on OCT was surprisingly not associated with FFR <0.80. The best overall OCT MLA cut-off was 2.0 mm2, with an area under the curve of 0.80; area stenosis was less helpful, with area under the curve of 0.73 for the best cut-off of 73% area stenosis. For proximal segments, however, the best cut-off was MLA = 3.1 mm2, and this had a reasonably predictive area under the curve of 0.85.
This study reinforces the results of prior studies with intravascular ultrasound (i.e., FIRST [Fractional Flow Reserve and Intravascular Ultrasound Relationship Study]) that anatomic cross-sectional measurements are limited in predicting the physiologic consequences of coronary stenoses. Although classically termed anatomic-physiologic mismatch, discordance between anatomic measurements and physiology are in part a function of the limited amount of anatomic detail that can be analyzed because lesion length, lesion morphology, and eccentricity are difficult to process. Even with an ideal system that imaged the entire coronary artery and incorporated side branches, the largest factor determining the FFR is the microcirculation and the size of the subtended bed, neither of which are assessed with imaging. Thus, the concept of a single or multiple anatomic cut-off value for lesion severity will always have some value, but this will always be limited compared with measuring physiology.
Insights From REDUCE-IT REVASC
By Peter L. Duffy, MD, MMM, FACC
Appalachian Regional Healthcare System
- A focused analysis of the REDUCE-IT trial demonstrated that icosapent ethyl 4 g/day reduced first and total revascularization respectively by 34% and 36% which was similar across urgent, emergent, and elective conditions.
- This represents the first major non-low-density-lipoprotein-cholesterol trial including statin therapy that reduced CABG surgery.
One of the most controversial topics in cardiology over the past several decades has been whether fish oil supplementsspecifically omega 3 fatty acidsexert a cardioprotective effect. Until the REDUCE-IT REVASC (Reduction of Revascularization in Patients with
Hypertriglyceridemia with Icosapent Ethyl) trial results, the consensus seemed to be that fish oil supplements were largely ineffective or minimally effective at best. At SCAI 2020, REDUCE-IT REVASC, a 5-year, focused analysis of the REDUCE-IT trial was presented, assessing the impact of icosapent ethyl on need for coronary revascularization.
REDUCE-IT randomized 8,179 patients over age 45 with persistently elevated triglycerides after at least 4 weeks of statin use to icosapent ethyl 4 g/day or placebo for an average of 5 years. Most patients had established cardiovascular disease (70%), with the remainder being deemed high risk (defined as diabetes and at least one other risk factor). The important difference in this trial was the quality of the fish oil used: icosapent ethyl is a prescription-grade fish oil with pure eicosapentaenoic acid.
Active treatment demonstrated absolute reductions of 3.3% in elective PCI, 0.6% for emergent PCI, 2.3% for urgent PCI, 4.1% for PCI overall, and 1.5% for CABG. For high-risk patients in the secondary prevention group, there was an absolute reduction in need for initial revascularization of 5.3% (16.7% vs. 11.4%).
These are astounding results and indicate tremendous potential for a medication that is generally well tolerated with minimal side effects to further reduce the need for high-cost, high-risk procedures while helping achieve the quadruple aim: an improved patient experience, an improved clinical experience, better outcomes, and lower cost.
The ESCAPE-CMD Trial
By Michael N. Young, MD, RPVI
Dartmouth-Hitchcock Medical Center
Geisel School of Medicine at Dartmouth
- ESCaPE-CMD (Exploratory Study of CLBS16 in Patients with CMD) demonstrated that intracoronary injection of CD34 cell therapy improved coronary microvascular flow with a reduction in angina frequency in patients with angina and microvascular dysfunction in the absence of significant coronary artery disease.
At the recent SCAI 2020, Dr. Timothy Henry and colleagues presented findings from ESCaPE-CMD as part of the late-breaking conference proceedings. ESCaPE-CMD is an interventional, open-label phase II study of patients with coronary microvascular dysfunction who underwent intracoronary infusion of autologous CD34+ cells. Coronary microvascular dysfunction may lead to severe angina due to underlying impaired microvascular dilatation, as well as endothelium-dependent coronary reactivity and constriction. Meanwhile, CD34+ is a naturally occurring progenitor endothelial cell that affects microvascular angiogenesis in ischemic tissues and may therefore offer a therapeutic role in the disease pathophysiology of coronary microvascular dysfunction. This cell line has also been studied in other cardiovascular disease conditions such as critical limb ischemia and systolic congestive heart failure.
In ESCaPE-CMD, 20 patients were enrolled at 2 large tertiary referral centers in the United States. These subjects received granulocyte colony-stimulating factor-mobilized autologous CD34+ cells (manufactured and processed by a proprietary entity) via direct injection into the left anterior descending coronary artery. Inclusion criteria were frequent angina (≥3 times weekly), no angiographically obstructive epicardial coronary disease, and intracoronary adenosine coronary flow reserve ≤2.5. Exclusion criteria included recent MI (<90 days), significant valvular disease, cardiomyopathy, and concomitant anticoagulation. The mean age of the study group was 54.3 ± 12.7 years. The majority of subjects was white (n = 16), female (n = 17), and on anti-anginal therapy. At 6 months, there was a significant improvement in coronary flow reserve from baseline (2.08 to 2.68; p = 0.0045). In this timeframe, there were also significant clinical improvements with respect to decreased anginal frequency (mean change -2.34; p = 0.0036), more favorable Canadian Cardiovascular Society angina class, and quality-of-life metrics based on Seattle Angina Questionnaire scores. Notably, one procedure did result in a coronary dissection that required stent implantation.
In this proof-of-concept study, patients with microvascular angina who received intracoronary infusion of an autologous CD34+ cell formulation derived significant improvement in measures of coronary flow reserve, angina, and quality of life out to 6 months. These data highlight a promising therapy for a subset of cardiac patients with limited options for symptom relief. However, it should be noted that this is a small study encompassing only 20 patients and, therefore, is exploratory in nature at this time. The investigators have alluded to plans for a larger randomized and blinded clinical trial down the line that will be highly anticipated given the ESCaPE-CMD results presented at SCAI 2020. Looking forward, pragmatic factors that would ultimately need to be addressed prior to clinical adoption and dissemination of this infusion therapy are safety, durability (i.e., permanence) of treatment effect, cost, and scalability. In particular, it will be important to ensure that the safety profile of therapeutic drug delivery is maximized given the one adverse intraprocedural event reported in the analysis. Otherwise, the early clinical improvements in the patient-reported outcomes are encouraging for this investigative drug therapy.
Keywords: Coronary Angiography, Coronary Artery Disease, COVID-19, ST Elevation Myocardial Infarction, Percutaneous Coronary Intervention, Angina, Stable, Tomography, Optical Coherence, Coronavirus, severe acute respiratory syndrome coronavirus 2, Microcirculation, Quality of Life, Constriction, Pathologic, Cost-Benefit Analysis, Microvascular Angina, Eicosapentaenoic Acid, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Fatty Acids, Omega-3, Fish Oils, Secondary Prevention, Risk Factors, Adenosine, Cardiovascular Diseases, Consensus, Benchmarking
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