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TCTAP & AP VALVES 2020 Virtual

The DEFINE-FLOW Study: Combined CFR and FFR Lesion Assessment

On August 6th, at the Highlight Session of TCTAP & AP VALVES 2020 VIRTUAL, Nils Johnson, MD (McGovern Medical School at UTHealth, Texas, USA) introduced ¡°DEFINE-FLOW¡¯ study with great expectation. As a result of several pivotal randomized controlled trials, fractional flow reserve (FFR) started to play a dominant role in physiologic assessment on an epicardial level. Although coronary flow reserve (CFR) can interrogate the entire coronary circulation on both epicardial and microcirculatory levels, it should be measured invasively using either Doppler flow velocity or thermodilution techniques. Considering the binary abnormal values of FFR ¡Â 0.8 and CFR < 2.0, FFR and CFR disagree in 30%-40% of cases. Prior literature regarding prognosis and revascularization necessity for these frequent discordant cases has been limited by the selection bias of treatment as well as its being retrospective and single-center design. As a result, uncertainty persists when faced with FFR and CFR discordance. To resolve this clinical uncertainty, Nils P. Johnson and his colleagues designed a nonrandomized nonblinded study named DEFINE-FLOW (Distal Evaluation of Functional performance with Intravascular sensors to assess the Narrowing Effect - combined pressure and Doppler FLOW velocity measurements). They hypothesized that lesions with an intact CFR ¡Ã 2.0 but reduced FFR ¡Â 0.8 will have a 2-year outcome with medical treatment similar to lesions with FFR > 0.80 and CFR ¡Ã 2.0, as based on previously conducted studies with a 10-year follow-up. PCI will only be performed immediately after intermediate lesion assessment when both binary FFR and CFR are abnormal; all other lesions will be deferred from revascularization to study their ¡°natural history¡± (Figure 2). The primary endpoint is the 24-month rate of major adverse cardiac events (MACE) defined as a composite of all-cause death, myocardial infarction (MI), unplanned or urgent revascularization, and elective revascularization. Specifically, the MACE rates will be compared in each discordant group (low FFR but intact CFR, intact FFR but low CFR) against lesions with intact FFR and CFR. They have completed enrollment of 455 subjects and started the follow-up on the clinical events. Details of study design and baseline characteristics of the fully enrolled cohort were published in American Heart Journal this April (Am Heart J 2020;222:139-46) and the results are expecting to be announced on this upcoming TCT 2020. DEFINE-FLOW will be able to show whether a simultaneous assessment of CFR offers independent prognostic and clinical values once FFR is known. William Fearon, MD (Stanford University School of Medicine, California, USA), a panelist, asked a question about the blindness of the operators/physicians and the adequate power calculations - small number of participants - of the DEFINE-FLOW study. Dr. Johnson replied, ¡°In order to adopt good Doppler signals, it is not practically possible for us to blind operators. Therefore, the operators are not blinded to the result, in fact, the CFR value have to be unblinded to have a uniform approach to treating lesions that had lower FFR values.¡±, ¡°To the second point, you¡¯re right. The study is going to be hypothesis generating for what to do with that group both FFR positive but CFR intact lesions. I think it's a steppingstone along that way to the definitive trial.¡± ¡°Plaques at those lesions with low FFR and high CFR are exposed to very high wall shear stress, that is associated with a vulnerable plaque formation. If you are going to plan a randomized trial for the patients with low FFR and high CFR, you may need a very long-term follow-up to integrate the influence of those wall shear stress.¡± Bon-Kwon Koo, MD (Seoul National University Hospital, Seoul, South Korea) commented. CHECK THE SESSION

August 07, 2020 13641

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TCTAP & AP VALVES 2020 Virtual

Imaging-guided PSP: How to Optimize Your Stent for Complex Coronary Lesions?

Percutaneous coronary intervention (PCI) for complex coronary artery disease such as left main, bifurcation, diffusely long, and severely calcified lesions has been increasingly performed because of increased longevity of the target population, enhanced pharmacotherapies, improved stents, and techniques. Nevertheless, it is still related to lesser favorable clinical outcomes than simple-lesion PCI. The role of intravascular imaging for optimal stenting for complex coronary lesions has been emphasized through recent clinical studies. Jung-Min Ahn, MD (Asan Medical Center, Seoul, Republic of Korea), presented his latest research of the intravascular imaging guided optimal stenting technique for complex lesions at the highlight session of TCTAP & AP VALVES 2020 VIRTUAL. The concept of optimal stenting was rejuvenated with the lesson from bioresorbable scaffolds intervention, needing standardizing pre-dilation, stent sizing, and post-dilation (PSP). Dr. Ahn and his colleagues introduced a concept of intravascular imaging guided PSP (iPSP), which integrating intravascular imaging to the classic PSP, and evaluated its role for patients with complex coronary artery lesions. He analyzed a registry data including 9,525 patients who underwent complex-lesion PCI at 42 hospitals in Korea between 2008 and 2017. Complex coronary lesions included left main stenosis, bifurcation, long lesions (30 mm or over) and severely calcified lesions. The iPSP technique was defined as consisting of 3 components: 1) pre-dilation, 2) intravascular imaging-guided stent sizing, 3) post-dilation using noncompliant balloons for complete stent expansion, which was confirmed by final intravascular imaging surveillance. Figure 1. The definition of imaging-guided PSP (iPSP) A complete iPSP strategy was performed in 3,374 patients (35.4%) whereas in 6,151 patients, 1 or more steps of the iPSP procedure were not performed. Patients treated according to the iPSP procedure were younger and included more men and of those who had hypertension, hyperlipidemia, and more complex and longer lesions compared with no-iPSP patients. To overcome differences between the two groups, he performed extensive statistical adjustment including propensity score-matching and inverse probability of treatment weighting (IPTW). The patients with complete iPSP received more (1.41 vs. 1.35, p

August 07, 2020 89193

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TCTAP & AP VALVES 2020 Virtual

1st Virtual TCTAP & AP VALVES 2020!

In last March, as COVID-19 pandemic became a reality, large-scale events at home and abroad were canceled one after another. Due to the nature of the infectious diseases that spread rapidly, every country limits the events that large numbers of people gather, and accordingly it is difficult to hold academic conferences normally. That is, it is actually impossible to hold an offline conference in the existing way of the face-to-face method. Worse yet, the COVID-19 era is expected to be prolonged, as there is a warning for the second wave of the pandemic this fall, while there is no promise for the end of COVID-19 and the completion of vaccine development. In the present situation, as demands for online consumption and education increase, and the contactless culture emerges as a trend, online academic conferences are being proposed as an alternative. The biggest advantage of online academic conferences is that the accessibility to high-quality content can be strengthened with no restrictions on time and place. Attendees can save travel time and freely participate by selecting the area that they are most interested in. When attending offline conferences, it can be regrettable that attendees cannot hear lectures conducted in different spaces at the same time, but this temporal and spatial limitation can be solved as well by the online method. On the other hand, it is pointed out that communication is not as smooth as offline events while the technical completion of video conference programs, live chat, VOD, etc., which are mainly used in online academic conferences, has somewhat improved. For speakers, they need skills to transfer their knowledge as well as to attract audiences online. However, it is difficult to immediately check reactions of thousands of connected audiences, so it seems necessary to build a system that allows many to communicate interactively. As the convenience and merit of online conferences are great, in the future, a hybrid-type conference applying 'Blended Learning', a concept that combines on/offline education, is expected to develop by complementing the shortcomings. Likewise the online conference is no longer a temporary phenomenon but a new normal after the COVID-19 pandemic, and the wind of change is also blowing in the institutional aspect. Overseas conferences including ones held in the United States, Europe, and Japan are expanding the recognition of training credits through online conferences, and as the recent discussions with the Ministry of Health and Welfare and the Korean Medical Association have made it possible to recognize the training credits and support e-booth in Korea, detailed guidelines are being prepared at the government level. In the light of the current trend of the academia and the social situation, CVRF decided to hold a new non-face-to-face online conference, instead of the previous face-to-face type, to overcome the discontinuity of academic exchange in the field of cardiovascular intervention. TCTAP and AP VALVES conferences, which were originally scheduled to be held in April and August this year respectively, will be held simultaneously in the name of TCTAP & AP VALVES 2020 Virtual in August. The coming conference will begin with addressing various issues related to COVID-19 with experts from around the world, and a discussion session on LM PCI vs. CABG and a highlight session examining Tape Case, TAVR, CTO, Pharmacology, CHIP & HBR, Stent technology, and Bifurcation will be prepared. In every session, experts on each subject will be invited to exchange questions and answers with participants via live chat. After the session ends, it is possible to watch the preferable session again through the VOD. In addition, abstracts and case sessions will be posted in electronic document form so that attendees can freely browse and share their opinions online. Moreover, TCTAP & AP VALVES 2020 Virtual Conference is spurring the construction of a convenient registration system for participants and a technical system to understand practical participation in sessions so that attendees can receive training credit for online education. As it is a new attempt based on the purpose of a wide range of academic exchanges, the registration fee of this conference is all free. For more information and details of the conference and programs, please check on the website (www.summit-tctap.com). For smooth session participation , it is recommended to register in advance on the website until August 5th. * Since 1995, CVRF has made continuous efforts to raise the level of medical and research on cardiovascular treatment to a global level through research and academic exchanges on cardiovascular disease and cardiovascular interventions at home and abroad. By holding academic conferences including TCTAP, AP VALVES, Complex PCI Society, etc., it has been developed into the international academic conference representing the Asia Pacific region.

July 24, 2020 104106

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SummitMD

Infectious Disease Expert Calls for Distinct Treatment Strategies for Heart Patients with COVID-19

The spread of the novel coronavirus (COVID-19) - known to worsen the prognosis for patients with cardiovascular and heart disease - should be deterred with non-pharmaceutical interventions until the development of a proven vaccine or antiviral, an infectious disease expert said. In an interview with summitMD, Professor Kim Sung-Han from Asan Medical Center, Infectious Diseases, Hematologic Cancer & BMT center outlined the problems of ICU bed shortages and potential risks to health care professionals during the pandemic while stressing that until vaccines or antivirals are available, use of personal protective equipment (PPE) and differentiated treatment strategies can save lives. Large Number Of COVID-19 Patients with Underlying Cardiovascular Disease Kim pointed towards several reports from the field that observed many COVID-19 patients had underlying cardiovascular conditions. A study from Wuhan, China1 on 191 patients showed that 48 percent of all patients had comorbidity. Researchers found 30 percent of all patients had hypertension (48 percent of non-survivors), 19 percent of all patients had diabetes (31 percent of non-survivors), and 8 percent had cardiovascular disease (13 percent in non-survivors). Another cohort of 138 hospitalized patients from Wuhan, China2 showed that comorbidities, and cardiovascular disease, in particular, were prevalent. About 45 percent of all patients and 72 percent of patients requiring intensive care unit (ICU) care had comorbidities. In addition, about 31 patients had hypertension (58 percent requiring ICU care), 15 percent had cardiovascular disease (25 percent of patients in ICU care) and 10 percent had diabetes (22 percent of those requiring ICU care). Concerning heart disease, 16.7 percent of patients developed arrhythmia and 7.2 percent experienced acute cardiac injury. Furthermore, an outpatient and inpatient cohort of 1,099 COVID-19 patients in mainland China3 showed that 24 percent of patients and 58 percent of patients with intubation or death had comorbidities. Hypertension was found in 15 percent (36 percent among those with intubation or death), diabetes in 7.4 percent (27 percent among those with intubation or death), and coronary heart disease in 2.5 percent (9 percent among those with intubation or death). Regarding these findings, Kim said "about 80 percent of COVID-19 patients experience mild disease or asymptomatic disease while about 15 percent experience severe illness, and the remaining 5 percent face critical illness. Of the critically ill patients, about half die. The risk factors for mortality are known as old age, comorbidities such as cardiovascular disease, lymphopenia, and higher LDH." SARS-Cov-2 Entry into Cells via ACE2 Increases Heart Patients' Vulnerability A study published in Circulation that analyzed the relationship between cardiovascular disease and COVID-19 stated that "[although] the mechanism of these associations remains unclear, potential explanations include cardiovascular disease being more prevalent in patients with advancing age, a functionally impaired immune system, or elevated levels of ACE2, or patients with CVD having a predisposition to COVID-19." The coronaviruses (CoVs) are a large group of single-strand RNA viruses that infect a broad range of species. These viruses are extensive in bats but can also be spread to other birds and mammals, including humans. In humans, CoVs can cause anything from the common cold (229E, OC43, NL63, and HKU1) to fatal respiratory illnesses that spread in human-to-human transmissions such as the Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). The most recent, and 7th known human coronavirus, SARS-CoV-2 (known as COVID-19), broke out in China in late December last year and has spread to more than 185 countries, causing millions of deaths. SARS-CoV-2 first attaches to human cells via the ACE2 receptor, and releases its RNA into the cell and creates virus replicates for its survival. Then, it leaves the host cell to enter other host cells. During this process, many host cells die from their direct cytopathic effect. The body's immune response, in which the host fights against the virus, also damages many infected cells as well as surrounding tissues which can in some instances lead to death. "Because ACE2 expression in the heart is highest in pericytes, SARS-CoV-2 may invade the pericytes and cause capillary endothelial cell dysfunction," Kim said. "The abundant expression of ACE2 by endothelial cells also can reduce its ability to prevent thrombosis upon entry of SARS-CoV-2 into cells." "Some excess cytokines during viral infection can also mediate myocardial injury. Underlying cardiovascular disease, as well as aging, also increased ACE2 receptor expression," Kim added. "So, it is possible that patients with cardiovascular disease might have more susceptible host cells for SARS-CoV-2 entry than patients without cardiovascular disease." Guidelines Recommend Screening, PPE, Treatment Although "No One Size Fits All" Studies on the relationship between underlying cardiovascular disease and mortality risk of COVID-19 has prompted medical societies to recommend guidelines on how to treat this particular subset of patients. Many guidelines focus on first screening for COVID-19, addressing safety concerns of both the patient and the medical team, and executing a treatment strategy that is unique to the pandemic. According to Society for Cardiovascular Angiography and Interventions (SCAI) president Ehtisham Mahmud, the problem that the pandemic brings to cardiology is two-fold. First, cardiovascular manifestations of COVID-19 are complex with patients presenting with AMI, myocarditis simulating an ST-elevation MI presentation, stress cardiomyopathy, non-ischemic cardiomyopathy, coronary spasm, or nonspecific myocardial injury. The second is that the prevalence of the COVID-19 disease in the U.S. remains unknown and there is the risk of asymptomatic spread. It is for these reasons that the ACC/SCAI recently recommended that elective cardiac procedures, particularly in patients with comorbidities, be pushed back during the COVID-19 outbreak considering the risks of infection in the hospital setting and patient safety. In a more comprehensive light, the European Society of Cardiology (ESC)4 recognized that "not one size fits all" since countries have varying levels of transmission. The ESC pointed out that in one study, about 41 percent of all infections were acquired infection in the hospital and more than 70 percent of these patients were health care professionals. Because the virus poses risk to health care professionals, the ESC guidance recommends protection against COVID-19 according to the level of risk based on patient presentation, types of procedures and interactions, as well as the risk status of health care professionals. In a cath lab where there are high rates of community infection, the ESC guidance heavily recommends wearing personal protective equipment as well as health care professionals donning surgical masks under the assumption that all patients are potentially infected. For patients with myocardial infarction with ST-segment elevation, the guidance notes that it might not be possible to wait for a nasopharyngeal swab result and recommends performing the procedure in a dedicated COVID-19 cath lab when available. For myocardial infarction with non-ST-segment elevation, high-risk patients should be treated under STEMI protocol and others should undergo a swab immediately after admission. If the test turns up positive, and an invasive approach is clinically indicated, the procedure should be performed in a dedicated COVID-19 cath lab. Balancing Act Between Feasibility and Safety As an expert in infectious diseases, Kim drew upon his experience on the ground, saying that "if the area has a high prevalence of COVID-19, screening for COVID-19 may be effective since many patients have asymptomatic infection." "However, in areas with a low prevalence of COVID-19, the screening test performed on patients with coronary disease may not be cost-effective," Kim said. "If physicians are not sure of the status of COVID-19 in heart patients, wearing personal protective equipment including masks, goggles, gloves, and gowns is recommended." "Shortage of ICU beds was common during the on-going COVID-19 outbreak," he added. In this regard, delaying elective surgery and procedures that require ICU admission is recommended but this recommendation should be balanced between available ICU beds and the harmful effect of the delaying procedures on the patients in given areas. Kim Sung-Han, MD Hope for Vaccine, and Utilizing Everything in Between To treat COVID-19, researchers around the globe have been interlocked in a race to find a cure. In this process, there has been much controversy over antiviral therapies, steroids, ACE inhibitors/ARBs, and drugs such as hydroxychloroquine. ACE inhibitors have been mired in scientific controversy over theoretical concerns that they improve conditions or cause harm. However, reassuring evidence is currently pointing towards antihypertensive drugs as safe. "The use of ARB or ACE inhibitors in patients with underlying heart diseases theoretically have beneficial or detrimental effects on COVID-19. Recent observational studies however have revealed that there is no harmful or beneficial effect of these antihypertensive agents on the development of COVID-19 or clinical outcome of COVID-19," Kim said. Although recent entries such as the steroid dexamethasone and the antiviral remdesivir are being tested in clinical trials - with positive results heralded in the media - Kim notes that there is yet to be a cure for the virus, recommending that until a vaccine is developed and distributed, non-pharmaceutical interventions are critical. "Currently, remdesivir is the only antiviral agent for severe COVID-19 patients that was demonstrated by a placebo-controlled randomized trial. There are no proven antiviral agents for mild COVID-19," Kim said. "Key factors to control the epidemic are antiviral agents to treat COVID-19 patients and vaccines to increase herd immunity but developing these require time," he added. "Until these are available, non-pharmaceutical interventions including social distancing and masks along hand hygiene are the most important measures for widespread prevention." Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054-1062. doi: 10.1016/S0140-6736(20)30566-3 Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323:1061-1069. doi: 10.1001/jama.2020.1585 https://www.nejm.org/doi/full/10.1056/NEJMoa2002032 https://www.escardio.org/Education/COVID-19-and-Cardiology/ESC-COVID-19-Guidance#p04 People photo created by prostooleh - www.freepik.com

June 26, 2020 5826

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SummitMD

Argument for RAAS Inhibitors¡¯ Safety During COVID-19 Pandemic Solidifies Despite Controversy

Despite the controversy, renin-angiotensin-aldosterone system (RAAS) inhibitors such as angiotensin receptor blockers (ARBs) and angiotensin-converting-enzyme (ACE) inhibitors are being proven safe to use during the COVID-19 pandemic by independent studies. The safety of RAAS inhibitors, which are used to control high blood pressure, came under scrutiny during the epidemic after reports out of China showed many COVID-19 patients had underlying comorbidities such as hypertension, and that these hypertensive COVID-19 patients fared poorly compared to those without high blood pressure. The issue was further aggravated when an influential Lancet paper raised theoretical concerns of antihypertensive medication raising risk of COVID-19 infection. As more researchers began weighing in on the issue with respective clinical findings, evidence is climbing towards RAAS inhibitors as being safe, compounded by medical societies urging hypertensive patients to continue taking the drugs. RAAS Inhibitor Controversy Ignites Over Conflicting Theoretical Concerns As early as February, researchers from Wuhan Institute of Virology, China unraveled in Nature1 how SARS-CoV-2 uses the ACE2 protein to enter cells, which is the same cell entry receptor as SARS-CoV. This finding was backed up by researchers from the German Primate Center2 who on April 16 outlined how SARS-CoV-2 uses the SARS-CoV receptor ACE2 to enter a host cell and the serine protease TMPRSS2 for spike protein priming. Researchers from the University Hospital Basel in Switzerland3 on March 11 raised concerns in The Lancet Respiratory Medicine that since treatment with ACE inhibitors and ARBs lead to an upregulation of ACE2, it would theoretically facilitate infection with COVID-19. According to the Swiss team, the concern with ACE inhibitors and ARBs is two-fold: one is that ACE inhibitors directly inhibit ACE2, and the second is that ACE inhibitors and ARBs increase expression of ACE2, thereby increasing patient vulnerability to the virus. Through this logic, the research team hypothesized that "diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19" and suggested that if patients with underlying conditions such as cardiac diseases, hypertension, or diabetes, are treated with ACE2-increasing drugs, it raises the risk for severe COVID-19 infection. Several animal studies in the pursuing week, however, suggested the exact opposite - hypertensive drugs might slow or stop inflammation in the lungs and have a protective effect in COVID-19 patients. As controversy and public confusion grew, researchers from Brigham and Women's Hospital in Boston, Massachusetts4 on March 4 pulled in the reigns on these two hypotheses, saying that "the significance of ACE2 expression on COVID-19 pathogenesis and mortality is not specifically known," adding that there is currently no evidence that proves ACE inhibitors and ARBs worsens or improves clinical outcomes in COVID-19. Medical societies then began uniformly releasing statements that recommended the continuation of RAAS inhibitor treatment for disease where its efficacy is proven. The European Society of Hypertension kicked off the statements on March 12 by making a strong recommendation for continuing treatment with antihypertensive therapy "because there is no clinical or scientific evidence to suggest that treatment with ACE inhibitors or ARBs should be discontinued because of the COVID-19 infection."5 The statement was followed by others from the Council on Hypertension of the European Society of Cardiology, Hypertension Canada, Canadian Cardiovascular Society, The Renal Association (U.K.), International Society of Hypertensive, American College of Physicians, Spanish Society of Hypertension, the Korean Society of Hypertension, and the British and Irish Hypertension Society, among others. Shortly after on March 17, the Heart Failure Society of America (HFSA), American College of Cardiology (ACC) and the American Heart Association (AHA)6 released a joint statement that stressed the controversy around hypertension drugs hinges upon an unproven theoretical concern and urged continuation of RAAS inhibitors for patients to effectively treat heart failure, hypertension, or ischemic heart disease until more clinical evidence was available. "Currently there are no experimental or clinical data demonstrating beneficial or adverse outcomes with background use of ACE inhibitors, ARBs or other RAAS antagonists in COVID-19 or among COVID-19 patients with a history of cardiovascular disease treated with such agents," the statement reads. "Therefore, be advised not to add or remove any RAAS-related treatments, beyond actions based on standard clinical practice." Major Studies Highlight Safety of RAAS Inhibitors As called for, researchers began rolling out studies that examined the safety of RAAS inhibitors in the COVID-19 landscape, heavily favoring the argument that patients should continue taking prescribed ACE inhibitors and ARBs for conditions such as hypertension. The first heavily cited NEJM paper7 conducted by Brigham and Women's University Hospital found that there was no harmful association of ACE inhibitors or ARBs and mortality. Although NEJM recently retracted the paper, experts still say that at least four other reputable papers from NEJM, The Lancet, and JAMA point towards the safety of RAAS inhibitors. NYU Langone cardiologist Harmony R. Reynolds' team8 found no association between any single antihypertensive medication class and an increased likelihood of a positive COVID-19 test in a NEJM paper published May 1, dispelling the notion that RAAS inhibitors increase the risk of infection. Likewise, Alcalá University's Francisco J de Abajo from Span concluded in The Lancet9 that "RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19." University of Milano-Bicocca's Giuseppe Mancia in Italy also reported that they did not see any associations between COVID-19 and ARBs (aOR 0.95, 95% CI 0.86~1.05) or ACE inhibitors (0.96, 95% CI 0.87~1.07). Additionally, Cleveland Clinic's Neil Mehta10 in JAMA Cardiology published data from a cohort study on 18,472 patients of whom 7.2 percent were taking ACE inhibitors and 5.3 percent were taking ARBs. Statistical analysis showed no association between ACE inhibitors or ARB use and testing for COVID-19 (OR 0.97, 95% CI 0.81~1.15). Mehta's team said the results backed "the various society guidelines to continue current treatment of chronic disease conditions with either ACE inhibitors or ARB during the COVID-19 pandemic." Now the latest data published in the European Heart Journal by Chinese researchers solidifies the argument for RAAS inhibitors during the COVID-19 crisis. According to Xijing Hospital's Chao Gao in China, hypertension patients were more likely to die during COVID-19 hospitalization (4.0% vs. 1.1% without hypertension, aHR 2.12, 95% CI 1.17~3.82). However, people with a history of hypertension who were not taking hypertensive medication were also more likely to die during hospitalization (7.9% vs. 3.2% on medications, aHR 2.17, 95% CI 1.03~4.57). When looking at medication class, RAAS inhibitors versus other antihypertensives produced similar mortality, although it was not statistically significant (2.2% vs. 3.6%, aHR 0.85, 95% CI 0.28~2.58). When the data was pooled with three other groups in China in a meta-analysis, RAAS inhibitors were associated with a significantly lower risk of mortality compared to other hypertensive drugs (RR 0.65, 95% CI 0.45~0.94). "While hypertension and the discontinuation of antihypertensive treatment are suspected to be related to increased risk of mortality, in this retrospective observational analysis, we did not detect any harm of RAAS inhibitors in patients infected with COVID-19," said Gao. "However, the results should be considered as exploratory and interpreted cautiously." Taken together, the evidence largely dispels the notion that RAAS inhibitors increase the risk of COVID-19 infection or worsens clinical outcomes of those affected. The deputy editor of the NEJM John Jarcho, MD and several coauthors drove the message home in an editorial,11 citing that there is not enough "evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among the infected, or the risk of in-hospital death among those with a positive test." Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. John Jarcho, MD https://www.nature.com/articles/s41586-020-2012-7 https://www.cell.com/cell/pdf/S0092-8674(20)30229-4.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420302294%3Fshowall%3Dtrue https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext#%20 https://jamanetwork.com/journals/jama/fullarticle/2763803?guestAccessKey=218e22b9-d784-4f2c-9ebf-23dae07a68c4&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=032420 https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19 https://www.nejm.org/doi/full/10.1056/NEJMoa2007621 https://www.nejm.org/doi/full/10.1056/NEJMoa2008975 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31030-8/fulltext https://jamanetwork.com/journals/jamacardiology/fullarticle/2765695 https://www.nejm.org/doi/full/10.1056/NEJMe2012924

June 26, 2020 5253

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SummitMD

[Q's For Author] Lead MAIN-COMPARE Author Hashes Out Study Insights

The 10-year MAIN-COMPARE study published by Korean researchers in February highlighted the importance of the SYNTAX score in predicting long-term benefits of coronary revascularization with PCI and CABG in patients with left main (LM) coronary artery disease and low-to-intermediate anatomic complexity.1 The research team, led by Professor Yoon Yong-hoon (Chungnam National University Hospital, Daejeon, South Korea) and Professor Park Duk-woo (Asan Medical Center, Seoul, South Korea), found that the 10-year risk for death and other clinical outcomes were similar between PCI and CABG, although PCI proved to be associated with a higher risk for death in patients with a high SYNTAX score. In light of these findings published in JACC: Cardiovascular Interventions, SUMMIT-MD met with lead study author Yoon to discuss major findings of MAIN-COMPARE, the EXCEL trial findings, and future possible studies. Q: What are the major findings of the MAIN-COMPARE study? Answer: We found long term-safety of PCI in LM disease patients with a low-to-intermediate SYNTAX score. However, all clinical outcomes favored CABG over PCI in the high SYNTAX score group. The SYNTAX score also had a prognostic ability only in the PCI arm, but not in the CABG arm. Q: What other insights does the MAIN-COMPARE study offer? A: The differential effect of CABG and PCI according to the SYNTAX score grade is caused by the mechanism of revascularization modalities. The CABG is immune to the state of atherosclerotic burden at proximal site to target lesion, because the grafts bypass tortuous angle, diffuse lesions, bifurcation, and calcification. Meanwhile, higher anatomic complexity requires more stents and complex techniques, which leads to a higher chance of restenosis in PCI. Q: Can you describe the study and how it compares to other trials that looked at PCI vs. CABG in LM coronary artery disease? A: The recently published long-term data from the SYNTAX trial produced similar results to MAIN-COMPARE. Both studies showed no difference in 10-year mortality in patients with a low-to-intermediate SYNTAX score, but higher mortality in those with a high SYNTAX score. The MAIN-COMPARE and SYNTAX trials both used first-generation drug-eluting stents, which may have contributed to producing similar results. The EXCEL and NOBEL trials, which produced longer-term outcomes using newer generation drug-eluting stents, may provide more information about the safety and efficacy of second-generation drug-eluting stents. Q: What is the importance of these novel findings and what are the clinical applications? A: To date, data regarding long-term outcomes of LM revascularization has been lacking. The treatment effect of two modalities differs over time, possibly due to factors such as the late catch-up phenomenon. In this regard, we needed long-term outcomes to guide patients to optimal treatment. The MAIN-COMPARE trial serves as valuable evidence for PCI as a safe and alternative option for LM disease, especially in the low-to-intermediate SYNTAX score population. Q: How would you interpret the findings from the EXCEL and NOBEL trials? The 5-year trials showed a limited discriminative capacity of the SYNTAX score in predicting differential outcomes after PCI and CABG. A: If you look at these trials in-depth, these landmark trials only enrolled a ¡°randomizable¡± population that had a low-to-intermediate SYNTAX score on-site. This resulted in a low number of patients with a high SYNTAX score in the core lab, and these patients were then categorized into low-to-intermediate SYNTAX score groups on-site. In these trials, the true population with a large atherosclerotic burden was low, and this may have led to a limited SYNTAX score capability. Q: What is the clinical application of the SYNTAX and SYNTAX-II score, and which is more important? A: There are two things to consider here. First is that only the anatomic complexity in coronary revascularization leads to unfavorable outcomes for patients. Second is that we all agree with the importance of age, LV ejection fraction, renal function, and other elements for the SYNTAX II score. In this regard, the SYNTAX II score may serve as better guidance for selecting an optimal revascularization strategy for LM disease. Q: When making decisions for multi-vessel or left main revascularization, do you routinely use the SYNTAX or SYNTAX II score in daily practice? A: We don¡¯t calculate SYNTAX score for every patient with LM or multi-vessel disease, but it is carefully considered when coronary lesions are thought to be within the range of an intermediate-to-high SYNTAX score and if the patient is open to two treatment options. This is because we all agree with the fact that the SYNTAX score is a reliable tool for guiding patients with LM or multi-vessel coronary disease. Q: Do you have any thoughts on the EXCEL trial controversy based on your study? A: It¡¯s important we interpret the recent EXCEL trial controversy carefully. Investigators observed higher mortality in the PCI group, and this may be because of the increased risk of repeat revascularization. Another aspect worth mentioning is that SYNTAX and MAIN-COMPARE showed no differences in mortality, so we need much longer-term outcomes to confirm the mortality risk. Q: How might your findings impact practice? A: In the past five years, we had little knowledge regarding the clinical prognosis of the two treatment options due to data scarcity. We can now perform PCI in patients with LM disease with a low-to-intermediate SYNTAX score with more evidence, having seen the long-term outcomes of similar safety results between PCI and CABG. We can discuss the results of the study with our patients and heart teams, which helps us decide the next course of action for patients to achieve better outcomes. Q: Are there any study limitations such as factors that would reduce the relevance of these findings for European or American patients? A: Even though we adjusted baseline clinical profiles of both PCI and CABG groups with inverse-probability-weighting analysis, this is not a randomized controlled trial. And the stents used in the study period (bare-metal stent and first-generation drug-eluting stent) are not used in current practice. So the study limitations would include the selection bias and used stent devices, which are currently not available. Q: What are your next steps? Will there be a follow-up analysis in the study population? A: I believe a 10-year follow-up would be enough to assess the long-term benefit of two coronary revascularization modalities. Going forward, we have to think about what further insight we can obtain from this population. Important factors such as age, sex, and LV ejection fraction, among others, can play a role in deciding on LM revascularization. To date, long-term outcomes regarding these factors are nonexistent. https://interventions.onlinejacc.org/content/13/3/361?_ga=2.3381232.171783738.1592270890-403549449.1592270890

June 12, 2020 3877

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STEMI Mimics, Safety Fears During COVID-19 Pandemic Spark Debate Over Fibrinolytic Use

Case-reports and anecdotal evidence are highlighting the rise of COVID-19 positive patients who present STEMI symptoms without arterial occlusion, sparking debate over whether to use the alternative therapy for coronary reperfusion. During the COVID-19 pandemic, reports have shown that COVID-19 patients had elevated troponin levels that indicate myocardial damage but no obstructive disease. Correspondence published in the New England Journal of Medicine on April 17 identified 18 COVID-19 patients at six New York-based hospitals with ST-segment elevation that indicated potential acute myocardial infarction. 1 Coronary angiography was performed on nine of the 18 patients. Of the nine, obstructive disease was observed only in six patients, leading the researchers to conclude that "there was variability in presentation, a high prevalence of nonobstructive disease, and a poor prognosis.." Another report from the research team led by Professor Giulio Stefanini from the Humanitas Clinical and Research Hospital IRCCS in Rozzano-Milan, Italy also observed frequent cases of non-ischemic causes of ST elevation among 28 COVID-19 patients treated at a cath lab in Lombardy, Italy – one of the most affected regions worldwide. 2 According to the retrospective case series, about 40 percent of STEMI patients who tested positive for COVID-19 did not have an identifiable culprit lesion via a coronary angiography. A coronary angiography confirming arterial occlusion showed that only 17 patients (60.7 percent) of the studied patients had major lesions requiring reperfusion. The remaining 11 patients (39 percent) had no arterial occlusion. The entire patient population underwent urgent angiography and none received fibrinolytic therapy. However, the research team noted that it was difficult to confirm the reason behind the STEMI mimics, pointing towards the possibility of a type 2 myocardial infarction, myocarditis caused by SARS-CoV-2 infection, endothelial dysfunction association with SARS-CoV-2, or a cytokine storm. To PCI or not to PCI? Dilemma of COVID-19 pandemic STEMI patients require coronary reperfusion therapy with primary percutaneous coronary intervention (PCI). Fibrinolytic therapy is an alternative when PCI is not feasible. However, these case-reports are currently complicating the argument for or against fibrinolytic therapy since applying fibrinolytics to COVID-19 infected patients with unobstructed arteries can worsen clinical outcomes by causing bleeding. The evidence stacked against fibrinolytic therapy as compared to primary PCI set the grounds for a dilemma wherein cardiologists have to weigh the risk of infection versus clinical outcomes during the COVID-19 pandemic. Although primary PCI has proved to be more suitable for STEMI patients, carrying out the procedure puts medical staff and patients at risk for COVID-19 infection. PCI may also not be feasible when hospitals are flooded with COVID-19 patients. In this particular time, hospitals may have to allocate cardiovascular disease experts to treating and managing infected patients. Accordingly, Professor Matthew J. Daniels from the University of Manchester, U.K. suggested fibrinolytic therapy may be considered as a primary treatment over primary PCI for STEMI patients who have symptoms within three hours and have no high-risk clinical findings in a Circulation paper on April 13. 3 The argument is that the COVID-19 crisis increases the total time to treatment, leading to delayed reperfusion since more time is consumed during the process of confirming a patient¡¯s medical history in the emergency room, tracing contacts, and carrying out additional tests to rule out COVID-19 patients, among others. In this case, Daniels noted that fibrinolytics may alleviate this problem by shortening the door-to-needle time while also protecting essential health care staff, including the cardiac intervention team. On the other hand, Stefanini who observed STEMI mimics on the ground made the opposing argument against fibrinolytic therapy. "Our findings show that STEMI may represent the first clinical manifestation of COVID-19," the research team wrote, warning that "in approximately 40 percent of COVID-19 patients with STEMI, a culprit lesion is not identifiable by coronary angiography.¡¯ "Our findings also show that a strategy relying on systematic fibrinolysis is not justified, since reperfusion appears not to be required in a significant proportion of COVID-19 patients with STEMI," they added. "A dedicated diagnostic pathway should be delineated for COVID-19 patients with STEMI, aimed at minimizing the patient¡¯s procedural risks and healthcare providers¡¯ risk of infection." ACC/SCAI/ACEP recommendations delineate "no fibrinolytic benefit" for STEMI mimics As the controversy continues, a joint recommendation from the American College of Cardiology (ACC), Society for Cardiovascular Angiography and Interventions (SCAI), and the American College of Emergency Physicians (ACEP) published in the Journal of American College of Cardiology (JACC) on April 20 pointed towards no fibrinolytic benefit for STEMI mimics. 4 The recommendation indicated that administrating fibrinolytic therapy to patients with STEMI mimics could cause bleeding while not resolving the problem of ST-segment elevation, ultimately leading to an invasive diagnostic test. Accordingly, the societies called upon PCI-centered medical centers to monitor whether they can proceed with timely primary PCI based on medical staff allocations and available personal protective equipment (PPE). Fibrinolytic therapy was recommended only when there was a lack of medical support. Experience from field stresses COVID-19 screening first, PCI second Professor Yan Li of Tangu Hospital in Xi¡¯an, China also outlined a treatment strategy for COVID-19 patients with suspected STEMI after treating patients during the most critical outbreak period in China on May 14 during a Live Webinar titled "China-Asia Pacific Interventional Cardiologists Facing COVID-19 as One." 5 According to Li, the cardiology department at Tangdu Hospital adhered to the "Chinese consensus," published in Circulation, to treat a total of 163 patients admitted with ACS and severe CVD disease. The Chinese consensus outlined the importance of triaging cardiovascular patients. Tangdu Hospital categorized patients into STEMI, hemodynamically stable STEMI without fibrinolytic therapy, and NSTEMI to apply a treatment strategy for each patient group. STEMI patients were first transported to a treatment facility and fibrinolytic therapy was performed under safety protection. After screening for COVID-19, patients were then transported to a PCI hospital. Hemodynamically stable STEMI patients were first screened for COVID-19, and PCI was performed if the patient tested negative for COVID-19. NSTEMI patients were also first screened for COVID-19 while medical professionals utilized level III PPE as needed. Unstable NSTEMI patients were treated according to STEMI patient protocol. "Assessing the benefits of COVID-19 treatment versus cardiovascular disease treatment was a key question for cardiologists at Tangdu Hospital when making treatment decisions," Li said. "AMI patients were common but they were difficult to treat during the COVID-19 epidemic." In light of all these findings, experts are highlighting the difficulties of executing PCI and staying within the appropriate door-to-balloon time frame during the pandemic, citing issues of hospital staff shortage, epidemiological investigations, and personal protective gear, among others. Because the decision to PCI is complicated by the fact that patients are presenting STEMI without obstructed arteries, experts are calling for a better strategy that improves upon the traditional treatment process. https://www.nejm.org/doi/full/10.1056/NEJMc2009020 https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.047525 https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2020/04/20/15/48/reperfusion-of-stemi-in-the-covid https://www.onlinejacc.org/content/accj/early/2020/04/23/j.jacc.2020.04.039.full.pdf http://arkadin1.gensee.com/webcast/site/vod/play-a88e82a16e3a4bcab71509b7504393c4

June 12, 2020 5086

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Clinical Evidence Mounts Toward Remdesivir As Potential COVID-19 Therapy

Six months into the pandemic and with no proven treatment in sight, remdesivir is rising as a potential therapeutic option for the patients with moderate COVID-19 after trials showed it sped up recovery with few adverse effects, although it did not slash mortality rates. Foster City, California-based Gilead Sciences originally developed remdesivir (GS-5734) as a treatment for Ebola, although it failed related clinical trials. Several studies had identified remdesivir as a potential candidate for COVID-19 therapeutics for its ability to inhibit SARS-CoV-2 in vitro. 1 The U.S. Food and Drug Administration (FDA) on May 1 approved remdesivir to treat confirmed COVID-19 in adults and children hospitalized with severe disease. 2 The decision came two days after the National Institutes of Health¡¯s (NIH) clinical trial showed ¡°promising¡± results. In the NIH study published in the New England Journal of Medicine (NEJM) on May 22, remdesivir pulled through in a double-blind, randomized, placebo-controlled trial by shortening the time to recovery from 15 to 11 days compared to placebo, although it did not improve mortality rates. 3 The multinational, multicenter, double-blind, randomized, placebo-control study – led by John H. Beigel, M.D. from the National Institute of Allergy and Infectious Diseases (NIAID) – compared the efficacy and safety of intravenous remdesivir versus a placebo on 1,063 patients. Included in the study were COVID-19 patients from 47 U.S. medical sites and 21 international institutions from Europe, Korea, Japan, and Singapore, among others. Patients were randomized into a remdesivir arm (n=538) and a control arm (n=521). In the remdesivir arm, investigators administered a 200 mg loading dose of intravenous remdesivir on day one followed by 100 mg daily for up to nine additional days. The placebo arm was administered placebo for 10 days. Investigators divided patients into eight categories based on factors such as hospital discharge as well as whether they required supplemental oxygen and ongoing medical care. The study included hospitalized patients requiring at least one of the following: supplemental oxygen, noninvasive ventilation, high-flow oxygen devices, invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). The primary endpoint was defined as the time to recovery, defined by either hospital discharge or hospitalization for infection-control purposes only. Investigators claimed that they did not define the mortality rate as the primary endpoint, considering that enrolling the prerequisite of 2,000 patients and recording at least 200 deaths was not feasible during the pandemic. Study results showed that remdesivir compared to placebo shortened time to recovery by 31 percent. Recovery time in the remdesivir arm totaled 11 days while the recovery time in the placebo arm amounted to 15 days (95% CI, 13~19). Kaplan-Meier estimates showed that the mortality rate in the remdesivir arm was 7.1 percent and 11.9 percent in the placebo arm at 14 days, yielding a statistically non-significant difference of 30 percent (HR 0.70, 95% CI 0.47~1.04). At the same time, the remdesivir arm reported fewer serious adverse events with side effects occurring in 114 out of 541 patients and the placebo group reporting side effects in 141 out of 522 patients. In line with these findings, Beigel¡¯s team reported that ¡°remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19 and [provided] evidence of lower respiratory tract infection.¡± The team also noted that the NIH trial design overcame limitations associated with two previously published remdesivir studies from Chinese researchers and Gilead Sciences. China-Japan Friendship Hospital¡¯s Yeming Wang, MD Department of Pulmonary and Critical Medicine, Center of Respiratory Medicine in Beijing, China published data from a randomized, double-blind, placebo-control multicenter trial of 10 hospitals in Hubei, China in The Lancet on April 29. 4 Wang¡¯s study showed that remdesivir did not demonstrate statistically significant clinical benefits. Clinical benefits encompassed time to clinical improvement within 28 days after randomization, defined as a two-point reduction in patients¡¯ admission status of a six-point ordinal scale, or discharge from the hospital – whichever came first. The trial was stopped early because of adverse events in 12 percent of patients in the remdesivir arm and 5 percent of patients in the placebo arm. However, NIH study investigators noted that Wang¡¯s study had around 240 patients, which was ¡°not enough¡± to assess efficacy. Gilead Sciences also published remdesivir data that looked at the efficacy of remdesivir in 5-days versus 10-days of treatment, without a placebo arm. 5 Study results showed that efficacy and adverse events in the two arms were similar, drawing media attention. NIH trial investigators again pointed out that there was no control group, thereby diminishing the significance of the findings. Having overcome these study design limitations, the NIH study now stress remdesivir as a treatment option for COVID-19. Adding to this pile of evidence is Gilead Sciences¡¯ phase 3 SIMPLE trial that reportedly demonstrated the efficacy and safety of remdesivir in COVID-19 patients with moderate disease. 6 The open-label study evaluated 5-day and 10-day courses of remdesivir plus standard of care, versus standard of care alone, demonstrating patients in the 5-day remdesivir treatment group were 65 percent more likely to have clinical improvement at day 11 compared with those in the standard of care group (OR 1.65, 95% CI 1.09-2.48, p=0.017). Gilead Sciences noted no new safety signals with remdesivir across either treatment group. Amidst the mounting evidence, the Ministry of Food and Drug Safety (MFDS) – South Korea¡¯s drug approving agency – announced on June 3 that it would import remdesivir to treat COVID-19 after approving a request from Korea Centers for Disease Control and Prevention¡¯s (KCDC) expert infectious disease panel. Prior to the approval, the KCDC on May 29 requested the MFDS import remdesivir under a specialized track that allows for drug imports in emergency situations without prior approval. ¡°The expert panel has evaluated remdesivir as a safe and effective drug for COVID-19 and affirmed the medical necessity of the drug in circumstances where there are no alternative anti-viral agents,¡° KCDC Director Jeong Eun-kyeong said. Despite the progress made, experts are noting that improvements can still be made, citing how anti-viral HIV therapies often go through a period of re-evaluation and development until the production of safe and effective drugs. Accordingly, more trials are underway to test remdesivir and a number of other drugs for COVID-19. 7 The NIH announced on May 8 that it would be rolling out a double-blind trial testing remdesivir with an anti-inflammatory drug baricitinib for COVID-19. The trial is expected to open at approximately 100 U.S. and international sites and enroll more than 1,000 participants. Baricitinib is a product licensed to Eli Lilly and Company by Incyte and marketed as Olumiant. Investigators will evaluate the time to recovery between a baricitinib plus remdesivir combination arm versus a remdesivir arm. Remdesivir will be administered as one 200 mg intravenous dose followed by 100 mg once-daily intravenous dose for the duration of hospitalization up to a 10-day total course of treatment. Baricitinib will be administered as 4 mg oral dose, or crushed and given through a nasogastric tube if necessary, for the duration of hospitalization up to a 14-day total course of treatment. ¡°We now have solid data showing that remdesivir diminishes to a modest degree the time to recovery for people hospitalized with COVID-19,¡± NIAID Director Anthony S. Fauci said in a press release. ¡°[This trial] will examine if adding an anti-inflammatory agent to the remdesivir regimen can provide additional benefit for patients, including improving mortality outcomes.¡± With the remdesivir trial in full swing, industry insiders are tracking whether remdesivir will demonstrate mortality benefits while hoping for developments of second or third generation of RNA-dependent RNA polymerase drugs based on remdesivir¡¯s proof-of-concept trial. Speculation and hopes aside, experts on the ground are stressing two points: more therapeutic options for COVID-19 need development, and more trials testing them need to be run. https://www.nature.com/articles/s41422-020-0282-0 https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment https://www.nejm.org/doi/full/10.1056/NEJMoa2007764 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext https://www.nejm.org/doi/full/10.1056/NEJMoa2015301 https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19 https://www.nih.gov/news-events/news-releases/nih-clinical-trial-testing-antiviral-remdesivir-plus-anti-inflammatory-drug-baricitinib-covid-19-begins

June 12, 2020 7283

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