Plasma, Ivermectin: Why Are India’s COVID Protocols So Dated?

7 min read

Concerned by the “irrational and non-scientific use of convalescent plasma for COVID-19,” clinicians, healthcare professionals, scientists and public health experts wrote an open letter to the Health Ministry, Indian Council of Medical Research and AIIMS.

The letter outlines three significant studies:

  1. ICMR-Placid Trial: The world’s first randomised control trial in 39 public and private hospitals in India which found that, “Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality.”
  2. Recovery Trial: A large trial of 11,588 patients in the UK which found no difference in death or proportion of patients discharged.
  3. PlasmAr Trial: This trial from Argentina found that “No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo.”

The US’s National Institute of Health and the Infectious Diseases Society of America also have recommendations against plasma at this time.

Dr Soumyadeep Bhaumik, a doctor and international public health specialist at The George Institute for Global Health, co-author of a study reviewing the Indian guidelines, and one of the signatories of the letter, says,

“Considering all these factors, the government guidelines are not really evidence-informed.”
Dr Soumyadeep Bhaumik

He adds, “As modern medicine doctors we distinguish ourselves by using clinical and research-based evidence to guide our work. Of course, this is not the only thing - evidence-based clinical decision making takes into account the skills of the doctor and the values and preferences of the patient and family.”


Why is the Government Not Following the Evidence?

How are guidelines developed globally?

They involve a series of steps.

“First, there are different trials conducted. There is an evidence review, what is also called a meta-analysis where you look at the literature, identify randomised trials and use statistical methods to pool the results to get one estimate for each outcome,” says Dr Bhaumik.

But there’s more. Dr Bhaumik adds that post this, a panel goes through the results and presents a framework called crede to understand how certain we are about the evidence. “The WHO uses the same methodology, this is the global standard,” he says.

Then it is put into the evidence to decision-making framework where it is adjusted according to the health systems capacities.

Dr Bhaumik says this empowers treating doctors to contextualise the guidelines as per the patient's needs and wants, and the hospital requirements. “We would like to see guidelines of international standard.”

“Putting up a flow-chart with no background documentation or saying which drug or therapy affects which outcome and by how much doesn’t help doctors make decisions. It’s a kind of copy-paste medicine rather than being able to optimise therapy as best for the patients. This is the number one problem with the AIIMS-ICMR guidelines”
Dr Soumyadeep Bhaumik

The AIIMS-ICMR website guidelines in the form of a flow-chart outlining the steps needed for the clinical management of COVID-19 in various scenarios.

Decoding ‘Off-Label Use’ in the Guidelines

The government guidelines also mention certain medication and therapies to be taken “in specific circumstances.”

“By definition, off-label means unapproved,” says Dr Bhaumik.

He explains what it means in clinical terms,

“Off-label traditionally means that I as a treating physician use a drug given for Y condition for treating X condition. It is not recommended but I believe it might help my patient. But we don’t understand what off-label would mean in the context of a guideline.”
Dr Soumyadeep Bhaumik

He explains how “even if we believe convalescent plasma works for arguments sake,” the two conditions mentioned in the guidelines do not make sense in the context of our health systems. “For plasma, it does not make sense for severe cases or those post 7 days, but there needs to be a test for both donor and patient to enable this treatment. How much of this testing is available across the country?”

“We are seeing a lack of consideration of these implementation or health systems issues. When recommendations are made without a discussion on the outcomes or all these issues, then doctors feel they need to do the best for their patient and families try their best as well. But what is the evidence behind this?”
Dr Soumyadeep Bhaumik

Dr Bhaumik adds that the guidelines need to be transparent as well, “Who is part of the guidelines and what are the conflicts of interest? Both democracy and medicine need transparency and accountability.”

Breaking Down Plasma Therapy, Ivermectin & Remdesivir

Despite having it on its guidelines for off-label use, The Indian Council of Medical Research (ICMR) had said that the “indiscriminate use of Convalescent Plasma Therapy (CPT) is not advisable,” after a new randomised study that found it did not lead to the reduction of the progression of severe COVID-19. As a potential treatment for patients with moderate COVID-19, convalescent plasma showed limited effectiveness.

Dr Sumit Ray HOD, Critical Care Medicine, Holy Family, Delhi says, “The theoretical benefit of plasma therapy is in helping boost immunity if not enough is developed in the patient. But, the problem with COVID-19 is not of an inadequate immune response, but in severe patients, the immune response goes haywire.”

One of the oft-repeated lines about plasma therapy is that it has been used in other diseases and therefore is safe. “But all diseases are not the same,” says Dr Ray. “Here you are giving plasma (which increases clotting) for a disease which is procoagulant or prone to causing clots.

“COVID is primarily a respiratory disease, and plasma treatment can often cause TRALY or transfusion-related acute lung injury. So if there is already lung damage due to COVID, and you give plasma which can cause - in a subset- further lung damage.”
Dr Sumit Ray HOD, Critical Care Medicine, Holy Family, Delhi

Furthermore, “Plasma therapy is normally given to increase clotting of the blood but in COVID-19 more clotting is already a problem - a pro-thrombotic state is on and we are giving blood thinners for the same,” says Dr Ray. So giving blood thinners and then plasma seems counter-intuitive for COVID-19 patients.

Dr Bhaumik says they are asking leading apex bodies to do a review of plasma and come up with evidence-informed guidelines.

  • Ivermectin

Ivermectin is a deworming drug used to treat and prevent parasites in animals, particularly in horses. In humans, it is used to treat certain intestinal and topical parasitic worms and skin conditions.

According to the WHO, It is also used in the treatment of scabies, onchocerciasis (river blindness), strongyloidiasis and other diseases caused by soil-transmitted helminthiasis.

In March of 2021, the WHO had previously already said that the current evidence on the use of ivermectin drug to treat COVID-19 patients is inconclusive, and recommended that the drug only be used within clinical trials. Currently, all major health authorities of the world, including the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) had discouraged the use of Ivermectin for the treatment of COVID.

Dr Chandrakant Lahariya, epidemiologist, and public health and policy expert, explains, "scientifically we know that ivermectin is an antiparasitic drug, whereas COVID 19 is a viral infection. So there is no plausible explanation for how an antiparasitic drug can treat COVID."

Dr Ray says, “The evidence for effectiveness is mixed. Some positive studies say it shortens the length of stay in hospital but doesn’t reduce mortality or the chance of patients going on ventilators. Even in the WHO Solidarity Trial, it did not show a positive result, only in some sub-group analysis was it shown to be effective - in some patients who were on minimal amounts of oxygen benefitted in terms of shortening hospital stay. Those who are not on oxygen do not benefit [from] reduction in the length of stay in hospital. For those on high oxygen support or on ventilators, this is not a life-saving drug.”

Chicken & Egg Situation

The current guidelines have added confusion and pressures on both sides. Doctors are under pressure to prescribe treatments like convalescent plasma therapy or drugs like Remdesivir despite evidence it isn't that effective. And relatives of patients, who see the shortages and deaths, go to any lengths to procure something that they assume can help.

It’s a vicious cycle, and Dr Ray tells me that he understands both the families and the doctor's side of things. “The families are desperate and will want to try anything, and doctors are under pressure by the highly publicised nature of these medicines and the general panic in the air.”

Both Dr Ray and Dr Bhaumik say the patients cannot be blamed right now as clear guidelines need to help reduce the panic.

“I know that people in this time want to try for everything they can - even if the evidence for effectiveness is not as strong,”
Dr Sumit Ray

‘Patients Rights Need to Be Preserved’: Ethical Medicine

“We have a paternalistic style of medicine in our country. If we think of it fairly, it’s MY body and if an intervention is being done I need to know. This is what shared-decision making is.”
Dr Soumyadeep Bhaumik

He concedes that a detailed discussion with the patient and families might not always be possible in a pandemic scenario, but “basic details like the side-effects and chances of benefits need to be shared. Being in a crisis does not mean we give our rights and ethics away even to a doctor.”

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