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• W2958977119 abstract "HomeCirculation ResearchVol. 124, No. 12More Data Than Options for the “No-Option” Refractory Angina Patient in the United States Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMore Data Than Options for the “No-Option” Refractory Angina Patient in the United States Robert F. Riley, Dean J. Kereiakes and Timothy D. Henry Robert F. RileyRobert F. Riley From the Christ Hospital Heart and Vascular Center / The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, Cincinnati, OH. Search for more papers by this author , Dean J. KereiakesDean J. Kereiakes From the Christ Hospital Heart and Vascular Center / The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, Cincinnati, OH. Search for more papers by this author and Timothy D. HenryTimothy D. Henry Correspondence to Timothy D. Henry, MD, Christ Hospital Heart and Vascular Center, 2123 Auburn Ave Suite 424, Cincinnati, OH 45219. Email E-mail Address: [email protected] From the Christ Hospital Heart and Vascular Center / The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, Cincinnati, OH. Search for more papers by this author Originally published6 Jun 2019https://doi.org/10.1161/CIRCRESAHA.119.315138Circulation Research. 2019;124:1689–1691This article is a commentary on the followingThe Impact of Cell Therapy on Cardiovascular Outcomes in Patients With Refractory AnginaThe prevalence and complexity of coronary artery disease are growing globally. Despite optimal medical therapy for coronary artery disease, including secondary prevention, and a renewed focus on complete revascularization, an increasing number of patients have refractory, lifestyle limiting angina.1–5 This patient population was formally defined by the European Society of Cardiology Joint Study group on the Treatment of Refractory Angina as patients with “a chronic condition caused by coronary insufficiency in the presence of coronary artery disease, which is not amenable to a combination of medical therapy, angioplasty, or coronary bypass surgery in patients with evidence of ischemia.”3 It has been estimated that 6% to 14% of patients undergoing diagnostic coronary angiography may meet this definition, but there is limited registry data and no coding data available.1,2,5,6 This patient group likely includes a combination of different phenotypes: those patients with incomplete revascularization, those with comorbidities or anatomy that precludes further revascularization, and those with microvascular dysfunction in addition to epicardial disease.Article, see p 1786How frequent is this problem? On the one hand, nearly 12 million patients have angina and based on the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation), 42% of patients in the optimal medical therapy arm and 34% in the percutaneous coronary intervention arm still had angina at one year.7 On the other hand, truly no-option refractory disabling angina (NORDA) patients with class III/IV angina that meet enrollment criteria for clinical trials are far less frequent. In fact, patients meeting this more stringent definition may qualify as an orphan population.8The care of these patients is challenging, especially given the lack of guideline-driven metrics for no option patients. Traditional treatments have focused on increasing myocardial blood flow, increasing the oxygen-carrying capacity of the blood, and decreasing myocardial oxygen demand. This may be achieved through a combination of revascularization for patients with obstructive epicardial coronary disease and medications (long-acting nitrates, calcium channel blockers, β-blockers, and ranolazine).1–4 Unfortunately, revascularization is frequently incomplete in the United States despite data supporting improvement in long-term major adverse cardiovascular events (MACE) in patients with complete versus incomplete revascularization.9 The only other approved therapies in the United States for these challenging patients are enhanced external counterpulsation, which can achieve modest reduction in anginal symptoms, but is logistically challenging, and transmyocardial laser revascularization, which may actually increase mortality.1–4Another controversial issue is the natural history or prognosis for these patients. Outcomes clearly depend on a number of factors including the extent of the disease, the degree of ischemia, left ventricular function, and comorbidities. Recent data indicate mortality has improved, but these patients remain at increased risk for MACE and quality of life is severely impaired.5Emerging therapies for this patient group include a renewed interest in complete revascularization (aided by improved techniques and tools to treat chronic total coronary occlusions), novel pharmacological agents, shockwave therapy, the coronary sinus occluder, therapeutic angiogenesis with cell or gene therapy, and neuromodulation.1–4 In this issue of Circulation Research, a systematic review and meta-analysis of randomized controlled trials evaluating stem cell-based therapies enrolling NORDA patients demonstrates a significant improvement in exercise tolerance, angina, and quality of life as well as a reduction in both MACE and mortality.10 Strong preclinical data indicate cell therapy promotes neorevascularization, improving myocardial perfusion, and thus relieving ischemia, which may also result in improvement of contractile function in ischemic tissues. Cell therapy is thought to exert paracrine effects via proangiogenic factors that can act locally to alter myocardial function, reduce apoptosis, and recruit resident and circulating stem cells.11 The current meta-analysis included 8 randomized controlled trials enrolling a total of 526 patients. Three cell types were included in these trials (CD133+, CD34+, and bone marrow mononuclear cells) and the majority were delivered via transmyocardial injection although one trial used intracoronary delivery. The authors reported a reduction in all-cause mortality in the treatment versus placebo/control groups (odds ratio, 0.24; 95% CI, 0.10–0.60) over the 6- to 24-month follow-up period reported in the trials. Similarly, MACE was reduced in the treatment group (odds ratio, 0.41; 95% CI, 0.25–0.70). In addition, they reported significant improvements in quality of life metrics for the cell-treated patients, including exercise time (+59.1 versus 26.2 seconds, P<0.01), angina class, angina episodes, anginal medication use, and quality of life measurements.10This meta-analysis provides additional support that cell therapy is a promising therapy for quality of life improvement in NORDA patients. This study also suggests again that cell therapy may provide improvement in long-term MACE as well as mortality. The CD34+ cell fraction appears to be an especially beneficial cell type based on a recent patient-level meta-analysis of 3 double-blind placebo-controlled trials, which demonstrated a reduction in angina, an improvement in exercise time, and a statistically significant reduction in mortality.12 In fact, the outcomes in this meta-analysis are driven primarily by the CD34+ data, which included 389/526 (74%) of the patients. Although available in several European countries, cell therapy delivered appropriately in a controlled environment is not yet available in the United States. This is also true for the novel pharmacological agents and interventional techniques—including the coronary sinus reducer,13 which are also available to some extent in European countries. This creates a dilemma for clinicians caring for patients with refractory angina. How do we provide safe and effective treatment options for the NORDA patient in the United States?Unfortunately, the pathway for approval and access to much needed novel therapeutics, including cell therapy, faces multiple challenges which include the limited number of patients qualifying for trial participation using strict NORDA definition(s), the requirement for randomization (often without a cross-over trial design) to placebo or sham procedures and the apparent reluctance of regulatory bodies to accept Bayesian study design (in contrast to trials of new drug-eluting stents) to facilitate accrual of power from prior, similar studies. Thus, cell therapy trials in NORDA patients have typically been rather small in size, difficult to enroll, and costly. Meta-analysis, although consistent in showing a reduction in mortality and MACE events and improvement in quality of life, must be viewed as hypothesis-generating.10,12 More importantly, all cell types are not equivalent. It might be argued that the cumulative sham/placebo experience in the NORDA population for CD34+ cells has been adequately defined to allow a single arm (nonrandomized) trial with an objective performance goal.8 Such a trial design could facilitate enrollment, reduce cost, and potentially expedite access to a treatment option(s) through optimal use of available data. Considering the guarded prognosis reported in NORDA patients (evidence the current meta-analysis) and in context of the limited current treatment options, a specific designation expedited pathway for regulatory approval might be reasonable. From a Food and Drug Administration perspective, the breakthrough designation has successfully shortened time to approval but principally for noncardiovascular indications.14 The 21st Century Cures Act, enacted in 2016, included the Early Feasibility Studies Program for cardiovascular devices. In addition, it included a pathway for Food and Drug Administration approval and market entry of regenerative therapies—the Regenerative Medicine Advanced Therapies designation.15 Although a number of regenerative therapies have been Regenerative Medicine Advanced Therapies designated, it is too early to know whether this will accelerate approval for cell therapies such as CD34+ for refractory angina.Despite the increasing ability to achieve complete coronary revascularization and novel treatments currently in various stages of development for patients with NORDA and microvascular disease/dysfunction, few options are currently readily available in the United States. Further, a comprehensive HEART team approach is warranted to coordinate care for this growing and challenging patient group (Figure). Similar to the HEART team approach used for structural heart disease, the HEART team for NORDA/microvascular angina should include physicians skilled at complex percutaneous and surgical coronary revascularization, imagers for diagnosing ischemia using various modalities (echo, nuclear, and coronary computed tomography), and clinicians specializing in patient-tailored medication regimens. Physicians caring for these patients should be knowledgeable about novel therapeutics such as cell therapy and coronary sinus occluders and willing to refer affected patients appropriately. Hopefully, more data will support the approval and availability of novel treatment options in the near future in the United States.Download figureDownload PowerPointFigure. HEART team approach to treating refractory angina. EECP indicates enhanced external counterpulsation.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Timothy D. Henry, MD, Christ Hospital Heart and Vascular Center, 2123 Auburn Ave Suite 424, Cincinnati, OH 45219. Email tim.[email protected]comReferences1. Henry TD, Satran D, Jolicoeur EM. Treatment of refractory angina in patients not suitable for revascularization.Nat Rev Cardiol. 2014; 11:78–95. doi: 10.1038/nrcardio.2013.200CrossrefMedlineGoogle Scholar2. Sainsbury PA, Fisher M, de Silva R. Alternative interventions for refractory angina.Heart. 2017; 103:1911–1922. doi: 10.1136/heartjnl-2015-308564CrossrefMedlineGoogle Scholar3. Mannheimer C, Camici P, Chester MR, Collins A, DeJongste M, Eliasson T, Follath F, Hellemans I, Herlitz J, Lüscher T, Pasic M, Thelle D. The problem of chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina.Eur Heart J. 2002; 23:355–370. doi: 10.1053/euhj.2001.2706CrossrefMedlineGoogle Scholar4. Jolicoeur EM, Henry TD. Refractory angina.de Lemos J, Omland T, eds. In: Chronic Coronary Disease: A Companion to Braunwald’s Heart Disease. Philadelphia, PA: Elsevier; 2018:P412–P432.Google Scholar5. Henry TD, Satran D, Hodges JS, Johnson RK, Poulose AK, Campbell AR, Garberich RF, Bart BA, Olson RE, Boisjolie CR, Harvey KL, Arndt TL, Traverse JH. Long-term survival in patients with refractory angina.Eur Heart J. 2013; 34:2683–2688. doi: 10.1093/eurheartj/eht165CrossrefMedlineGoogle Scholar6. Williams B, Menon M, Satran D, Hayward D, Hodges JS, Burke MN, Johnson RK, Poulose AK, Traverse JH, Henry TD. Patients with coronary artery disease not amenable to traditional revascularization: prevalence and 3-year mortality.Catheter Cardiovasc Interv. 2010; 75:886–891. doi: 10.1002/ccd.22431MedlineGoogle Scholar7. Boden WE, O’Rourke RA, Teo KK, et al; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease.N Engl J Med. 2007; 356:1503–1516. doi: 10.1056/NEJMoa070829CrossrefMedlineGoogle Scholar8. Benck L, Henry TD. CD34+ cell therapy for no-option refractory disabling angina: time for FDA approval?Cardiovasc Revasc Med. 2019; 20:177–178. doi: 10.1016/j.carrev.2019.01.012CrossrefMedlineGoogle Scholar9. Hannan EL, Zhong Y, Berger PB, Jacobs AK, Walford G, Ling FSK, Venditti FJ, King SBAssociation of coronary vessel characteristics with outcome in patients with percutaneous coronary interventions with incomplete revascularization.JAMA Cardiol. 2018; 3:123–130. doi: 10.1001/jamacardio.2017.4787CrossrefMedlineGoogle Scholar10. Jones DA, Weerama D, Colicchia M, Hussain MA, Veerapen D, Andiapen M, Rathod KS, Baumbach A, Mathur A. The impact of cell therapy on cardiovascular outcomes in patients with refractory angina: an updated systematic review and meta-analysis of randomized controlled trials.Circ Res. 2019; 124:1786–1795. doi: 10.1161/CIRCRESAHA.118.314118LinkGoogle Scholar11. Losordo DW, Dimmeler S. Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies.Circulation. 2004; 109:2692–2697. doi: 10.1161/01.CIR.0000128596.49339.05LinkGoogle Scholar12. Henry TD, Losordo DW, Traverse JH, Schatz RA, Jolicoeur EM, Schaer GL, Clare R, Chiswell K, White CJ, Fortuin FD, Kereiakes DJ, Zeiher AM, Sherman W, Hunt AS, Povsic TJ. Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials.Eur Heart J. 2018; 39:2208–2216. doi: 10.1093/eurheartj/ehx764CrossrefMedlineGoogle Scholar13. Verheye S, Jolicœur EM, Behan MW, et al. Efficacy of a device to narrow the coronary sinus in refractory angina.N Engl J Med. 2015; 372:519–527. doi: 10.1056/NEJMoa1402556CrossrefMedlineGoogle Scholar14. Darrow JJ, Avorn J, Kesselheim AS. The FDA breakthrough-drug designation - four years of experience.N Engl J Med. 2018; 378:1444–1453. doi: 10.1056/NEJMhpr1713338CrossrefMedlineGoogle Scholar15. Holmes DR, Hance R, Syrek Jensen TS, Schwartz DA, Kaplan A, Farb A, Zuckerman B, Leon M, Waklowiak J, Mack MJ, Shuren J. The 21st century cures act and early feasibility studies for cardiovascular devices: what have we learned, where do we need to go?JACC Cardiovasc Interv. 2018; 11:2220–2225. doi: 10.1016/j.jcin.2018.05.010CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Lantz R, Quesada O, Mattingly G and Henry T (2022) Contemporary Management of Refractory Angina, Interventional Cardiology Clinics, 10.1016/j.iccl.2022.03.002, 11:3, (279-292), Online publication date: 1-Jul-2022. Ryan C, Patel V and Rosengart T (2021) Clinical potential of angiogenic therapy and cellular reprogramming, JTCVS Open, 10.1016/j.xjon.2020.12.023, 6, (108-115), Online publication date: 1-Jun-2021. Povsic T, Henry T and Ohman E (2021) Therapeutic Approaches for the No-Option Refractory Angina Patient, Circulation: Cardiovascular Interventions, 14:2, Online publication date: 1-Feb-2021. Jolicoeur E and Henry T (2019) The cost of angina: how do we measure it? How do we improve it?, European Heart Journal - Quality of Care and Clinical Outcomes, 10.1093/ehjqcco/qcz058 Riley R, Kereiakes D and Henry T (2019) Response by Riley et al to Letter Regarding Article, “More Data Than Options for the ‘No-Option’ Refractory Angina Patient in the United States”, Circulation Research, 125:9, (e42-e42), Online publication date: 11-Oct-2019.Picichè M and Versaci F (2019) Letter by Picichè and Versaci Regarding Article, “More Data Than Options for the ‘No-Option’ Refractory Angina Patient in the United States”, Circulation Research, 125:9, (e40-e41), Online publication date: 11-Oct-2019.Related articlesThe Impact of Cell Therapy on Cardiovascular Outcomes in Patients With Refractory AnginaDaniel A. Jones, et al. Circulation Research. 2019;124:1786-1795 June 7, 2019Vol 124, Issue 12 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.119.315138PMID: 31170056 Originally publishedJune 6, 2019 Keywordscoronary artery diseasecell therapyrefractory anginastem cellrevascularizationEditorialangioplastyPDF download Advertisement SubjectsAnginaCell TherapyCoronary Artery DiseaseRevascularizationStem Cells" @default.
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