CME INDIA Presentation by Admin.

To be clear, sensible medicine does not mean clinicians should not intervene. Rather, it proposes a gentler, moderate, and humble view of available treatment options and their effectiveness in patients with COVID-19. In the middle is a sensible approach, which acknowledges that some interventions are effective but, perhaps, confidence should be tempered. With sensible medicine, the translation of knowledge to the bedside is appropriately calibrated to the rigor and reasoning of the available evidence and the severity of the outcome to be avoided. – Christopher W. Seymour, MD, MSc, Associate Editor, JAMA/ Erin K. McCreary.

Scenario 1. October 8, 2020, NEJM

Final Results of Remdesivir Trial Show Superior Efficacy for Treatment of COVID-19

• The final results of a trial investigating remdesivir has found that the drug shows superior efficacy compared with a placebo, resulting in a 5-day faster recovery and reduced disease progression.
• This double-blind, randomized, placebo-controlled trial identified an antiviral therapy as beneficial in the treatment of COVID-19.
• Overall findings were consistent with the findings of the preliminary report: a 10-day course of remdesivir was superior to placebo in the treatment of hospitalized patients with COVID-19
• Patients who received remdesivir had a shorter time to recovery (the primary end point) than those who received placebo (median, 10 days vs. 15 days.
• It indicated that journey with remdesivir has entered a new phase, with the potential to make an even greater impact on the pandemic.

Scenario 2. October 16, 2020, WHO SOLIDARITY TRIAL

• Remdesivir, the only antiviral drug authorized for treatment of COVID-19 in the US, fails to prevent deaths among patients, according to a study of more than 11,000 people in 30 countries sponsored by the World Health Organization.
• This puts the issue to rest — there is certainly no mortality benefit – Dr Ilan Schwartz, Canada.
• For Remdesivir this study provides more than three-quarters of the evidence.
• In discussion part authors of the trial say: Interpretation should chiefly reflect not the p-value (p=0.21) or point estimate (RR=0.91) but the confidence interval (0.79-1.05), which shows the range of death rate ratios comfortably compatible with the weighted average of the findings from all trials.
• This absolutely excludes the suggestion that Remdesivir can prevent a substantial fraction of all deaths.
• Solidarity Trial proves inefficacy of all four antiviral agents including Remdesivir

CME INDIA Discussion

Dr N K Singh: Do you think, it will change the practice trend…

These days, everywhere, it’s early use is being observed. Even at home. Those who are using early, say it is very useful. We do not know, if given early and given late – MAKES all the difference?

Dr Basab Ghosh, Agartala:  Antiviral in the first week, best within 5 days of first symptoms, is having best results as observed by experts on treating patients!

Dr Pradeep Sahay, Giridih: The early bird gets the worm.😊

Dr Ambrish Mithal, DM Endo., Delhi:

• Our hopes from medications for corona are unrealistic.
• Are we over-medicating patients especially those with mild disease? I think so.
• Both patients and doctor’s anxiety are contributing to this.
• I repeat – how do we treat usual Viral fever? Do we use antibiotics or antivirals?
• Because of the seriousness of storm and hypoxia induced by COVID, steroids and oxygen work. Also, anti-thrombosis agents, if indicated. Regular monitoring of inflammatory markers and d DIMER in patients being treated at home, along with paracetamol and Montelukast/ cetirizine if indicated is what we need. Further intervention if there is significant deviation in the markers. And of course, clinical signs, plus lung imaging when needed.
• Basically, the decisions to be taken for every patient are:
  • Are steroids indicated?
  • Is hospitalisation/oxygen Indicated?
  • Are anti thrombotic agents indicated?
• Rest we can continue to use based on our experience but I am not sure they are helping our patients.

Dr Shashank Joshi DM Endo, Mumbai: Agreed

Dr Prasun Dev, KIMS Hyderabad: Agree, sir. Probably nothing more than paracetamol and multivitamins for no/mild symptoms…. D, zinc, the whole nine yards…🙂

Dr Deepak K Singh, Ranchi: Yes, it is hotline of business news. All drugs marketing Remdesivir has sharp fall. So now which drug to support?

Dr A K Singh, DM Endo., Kolkata: No one will listen to it. These papers and evidence have no value in India when compared to anecdotal/my experience. Hope you remember HCQ fiasco and now it’s time of failed Remdesivir debate!

Dr N K Singh: As far as Remdesivir is concerned. It showed no benefit in hospitalised patients in solidarity trial.

Physicians Ponder:

Had it been started after day 3 or day 4 with increased inflammatory markers and CT findings. Then, what might have been the result? All Indian COVID centres are using Remdesivir extensively, some places 100% in hospitalised patients. We do not have our own randomized data?

Some comments to Ponder (NY)

▪️Dr Peter Chin-Hong, infectious-disease expert at the University of California, San Francisco:

“A huge trial like this one, conducted in various countries with various health care systems, can lead to inconsistent treatment protocols whose effects can be difficult to analyse.”

▪️Gilead experts…

“Because of its design, there was “significant heterogeneity” in the way the trial was conducted. “Consequently, it is unclear if any conclusive findings can be drawn from the study results.”

Dr Maricar Malinis, an infectious disease physician at Yale University:

Remdesivir findings aren’t terribly surprising based on previous findings, but they are “still impactful,” especially given the dizzying size of the Solidarity trial.

Both Dr. Schwartz and Dr. Maricar noted that remdesivir might still benefit people with COVID-19 earlier in the course of their illness. Severe COVID-19 is thought to be driven largely by an overly exuberant immune response that starts several days after the virus infects the body. Before that happens, an antiviral might tamp down the virus enough to protect a person from the immune system’s friendly fire. Administering remdesivir after that point may be pointless. “The horse is out of the barn.”

Dr Deepak Jumani, Mumbai:

• COVID virus and its treatment is full of uncertainty, ubiquitous, varied, and still lots to be learnt.
• Symptomatic patients have negative reports.
• Positive reported patients are asymptomatic.

Dr Ritesh Chaudhary, Diabetologist, Kanpur: Yes. End result is patient should return home alive.

Dr Manohar K N, Bengaluru: How about a poll – GOD forbid, we get this infection will we be okay to take Remdesivir?

Dr Ambrish Mithal, DM Endo., Delhi:  Ok to take is different from “will it really help?”

Dr A K Singh DM Endo., Kolkata: Let me explain it in detail…

1. 4 RCTs conducted so far in COVID with results on Remdesivir – SIMPLE/Wuhan/ACTT/Solidarity.
2. Barring SIMPLE other 3 RCT were divided into – a. Pt not on O2 b. Low O2 c. High flow O2 d. on Ventilations.
3. In SIMPLE trial: no one was on O2 (mild symptoms or asymptomatic) – results: no benefit.
4. In Wuhan RCT: 2 arms – a. Low O2, b. High O2 or ventilation – no benefit with remdesivir in any arm.
5. ACTT: 4 arms as mentioned in bullet no 2 – no benefit in any arm.
6. Solidarity: no benefit in any 3 arms.

Finally, the meta-analysis of:

1. All the 4 RCTs Pooled together with Remdesivir – no benefit
2. Two subgroups of
   • No or low O2: no benefit
   • High O2/ventilation: no benefit

Summary: No benefits of Remdesivir what so ever noted in any groups of COVID – asymptomatic/mild/moderate/severe/critical.

Dr Subrahmanyam Karuturi, Rajahmundry, AP: (Shared) This is where Remdesivir stands:

Dr Murali Mohan, Interventional Pulmonologist, Bengaluru: To me sounds ambiguous – let me phrase it…

(Shares for academic purpose only, from Solidarity trial)

When data is pooled and compared, you cannot use dissimilar groups who received different treatments at different times. More data is not more accurate data. The Forest plot above has not looked at the subgroups. The Forest plot I posted earlier in another group (API-Bengaluru) separates out the low/no O2 and the high O2/ mechanical ventilation subgroups. And the largest group with low oxygen did better though the CI just spilt over the zero-effect line.

Dr Vinay Dhandhania, Diabetologist, Ranchi: I don’t think there any intensivist in COVID hospital not using Remdesivir. Almost every hospitalised patient in ICU with COVID is getting Remdesivir and Dexamethasone. Some even tocilizumab. And percentage mortality from COVID in our country is much less. I don’t disagree from the data.

Dr Swati Srivastava, Asso. Prof., SMS Med College, Jaipur: Yes, it is being used left right centre. Particularly the VIPs, they get admitted just for free remdesivir course…. this includes many docs too…. almost all doctors who are positive have taken it. We divide patients depending on their severity Those moderate to severe get parenteral treatment. These include remdesivir, dexona, LMWH.

Those in mild group get oral azithromycin, vitamins +/- HCQS. This is an institutional protocol. We are bound to follow protocol. Now it seems it should be revised considering the solid evidence. Definitely, a lot of finances have been drained futile.

Dr S K Goenka, Begusarai: This protocol has become a trend and nobody wants to deviate from the set trend.

Dr V Dhandhania, Ranchi:  This is not a trend. This is in ICMR protocol.

Dr Anil Motta, Max, Sr Consultant Medicine, Delhi: It won’t be at all easy to deviate. Lot of idiosyncrasies. many not under personal control of individual doctors-howsoever rational!

Dr Hem Shankar Sharma, Asso. Prof. Med., Medical College, Bhagalpur: Ramdesivir is not a magic bullet, but if used within first 7 days of the onset of symptoms, moderate intensity or more, minimize the gravity of the problem. Oxygen requirements goes down, but changes of HRCT, are not affected remarkably.

Overall mortality benefits are questionable. I have lost cases, despite earlier treatment, within 7 to 8 days after the onset of symptoms, and completing the treatment in next 5 days, death occurred by 12 to 14 days, although they were diabetic!!

Dr Raj Kamal Chaudhary, Asso. Prof. Med., Bhagalpur Medical College: We tried Remdesivir 200 mg 1 st day ,100 mg on subsequent days for 2 days in Positive patients of COVID-19. We got good Results in 1 Patient but got Negative Results in around 50 Patients in ICU Of JLNMCH BHAGALPUR.

We have tried this drug with patients who came within 5 days and who did not have CKD those who had Oxygen Saturation within 80 to 94 % and they improved in Oxygen Saturation within a week but not in other symptoms. Almost the Age groups were from young to old but no benefit was found with Remdesivir while Patients were saved of above 80 years by simple injection of Meropenem, Oxygen Support, Dexamethasone, Enoxaparin.

So, my conclusion for Remdesivir was Not Positive.

Dr Akash Kumar Singh, Internist, Vadodara: Our centre’s experience with Remdesivir:

• We have been using Remdesivir at our centre as soon as it arrived in the Market and we have our observations in place with the Molecule.
• We will be in a better position to comment as we are doing a prospective ethics committee approved study of COVID19 patients admitted in our set up since June 2020 and the huge work of data entry is in process. Our team of myself, Dr. Kiran Shah (senior consultant, Dept. of Medicine) and our chief intensivist Dr. Ankur Bhavsar have the following observations.
• We definitely feel that it is a useful molecule for viral clearance and improvement in the medical condition of our patients given early on in the course of disease.
• Although the criteria are in favour of its use in patients on increasing oxygen requirement, we like to start it early even before oxygen is started, as the oxygen levels start dropping below 95% or so especially in those patients who are having 6-minute walk test positive.
• We definitely have good experience with the molecule given early on in the course of disease where we feel it is superior to Favirapavir. However, majority of the patients who are on remdesivir are also on steroids and heparin concomitant therapy. So, to tease out the individual benefit of remdesivir would be possible only after we do analysis of our data which may take another 4-5 months.
• However, it does not seem to help in those with higher oxygen requirement where we feel steroids take the onus of salvaging the patients.
• We also like to use it upfront in our doctors and paramedical staff who are supposedly exposed to higher viral load to effect faster viral clearance due to our belief that it is presently the best available drug to eliminate the COVID-19 viruses and decrease viral load thus leading to lower risk of morbidity and mortality in this high-risk population. We have unfortunate deaths in medical community when this molecule was not available but fortunately in the last couple of months, we have a significant decline in COVID19 related mortality amongst medical fraternity.
• However, if we have to summarise our experience with Remdesivir, we would say that it is a good molecule, use it early as the saturations starts to decline (Earlier than the oxygen requiring stage especially if 6 minute walk test is positive), with steroids and heparin along with it as per your decision individualised to your patient and wait for 3-4 days for the clinical improvement.
• If clinical improvement does not occur during this period, add other therapies like convalescent plasma, immunomodulatory drugs. However, used after the patient desaturates with higher oxygen requirement, it may not help.

CME INDIA Learning Points

• Given the preliminary results about remdesivir, FDA issued an Emergency Use Authorization on May 1, 2020 (modified on August 28, 2020), to permit the use of remdesivir for treatment in adults and children hospitalized with suspected or laboratory-confirmed COVID-19.
• Remdesivir has also received full or conditional approval in several other countries since that time.
• We need a variety of therapeutic approaches including novel antivirals, modifiers of the immune response or other intrinsic pathways, and combination approaches are needed to continue to improve outcomes in patients with COVID-19.
• At present, Solidarity trial has given a serious blow to Remdesivir, but it appears that its use will continue based on expert opinions and experiences.

CME INDIA Tail Piece (from source 3)

• COVID-19 is a potentially lethal combination of immunopathogenic and immunoprotective responses on a backdrop of a prothrombotic milieu.
• No single mechanism or pathway yet discovered accounts for all of the pathophysiology. Similar to acute respiratory distress syndrome caused by sepsis or trauma, a single mechanism or pathway is unlikely to be found. To date, only nonselective and mechanism agnostic drugs like corticosteroids or antiviral medications have been associated with an improved course in patients with severe COVID-19.
• To be sensible, clinicians must recognize that highly selective, fully effective treatments are uncommon in acute care.
• Focus on High-Quality Evidence. Some clinical research is biased. Even the best research methods, such as randomized trials, can be unreliable. This has been amplified by the rapid pace of research undertaken during the COVID-19.
• It follows that treatment guidelines, national mandates, and bedside care – adapt to new data only when the evidence is rigorous, reproducible, and sufficiently strong.

Source:

1. Remdesivir for the Treatment of COVID-19 — Final Report,October 8, 2020. DOI: 10.1056/NEJMoa2007764 https://www.nejm.org/doi/full/10.1056/NEJMoa2007764
2. Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results.doi: https://doi.org/10.1101/2020.10.15.20209817
3. JAMA Published online October 15, 2020. Sensible Medicine – Balancing Intervention and Inaction During the COVID-19 Pandemic. doi:10.1001/jama.2020.20271

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