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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

June 26, 2020 5537

[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.

June 12, 2020 4108

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.

June 12, 2020 5403

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.