Evidence: The bedrock of Covid management
Don’t promote poorly evaluated treatment as cures. The right care at the right time for the right patient is essential
Twitter in India is a desperate place. Pleas for beds, sources of oxygen, remdesivir and plasma overwhelm, even as volunteers amplify messages and scramble to help. Tongue twisters — tocilizumab, itolizumab — appear in discussion as people call, message and sink into despair and guilt at being unable to procure what they are told is needed to care for their family or friend.
We are struggling with a health care system that is inequitable in access and quality at the best of times. There is limited surge capacity for seasonal illnesses in hospitals, few trained and competent staff, especially in infectious diseases and critical care, and a fragmented health care system. At any time, and especially now, evidence-based medicine, or “the right care at the right time to the right patient” is essential.
As the Indian medical community and health policymakers, we have not done well in this pandemic. We have promoted, as “cures”, poorly evaluated treatments from our traditional systems of medicine. This is a disservice to the accrued knowledge over millennia of the science of life in Indian systems of medicine.
We have held on to “expert opinion” for drugs such as hydroxychloroquine, even as data continued to emerge from randomised controlled trials that it did not work. Guidance from the National Covid-19 Task Force from last week treats as equivalent “may do” recommendations, hydroxychloroquine, for which data from the Together trial in outpatients and the World Health Organization (WHO) Solidarity trial in inpatients show lack of benefit, and inhaled budesonide, which is supported at least by the open label Stoic trial and showed less progression to need for hospitalisation and less time to recover.
Evidence-based medicine requires lifelong learning, and the continued education of medical communities and patients. For a new infectious disease where we have little knowledge of how damage is caused and how to manage or reverse it, it is important to focus on the generation of evidence by testing old and new drugs and medical management measures.
Early in the course of the Sars-CoV2 pandemic, we relied heavily on information emerging from China where it appeared that we would need early and intensive ventilatory support, and many clinical trials were supported for antivirals and other drugs. Through the experience of pulmonologists and critical care specialists, we now know that keeping patients off ventilators for as long as possible makes it feasible to manage many with oxygen masks, high-flow nasal cannulas or non-invasive ventilation, moving to invasive ventilation as a last resort. Whether it is proning or ventilation, these were not situations where the treatment could be hidden from the patient or the doctor, so blinded or controlled and randomised clinical trials were not feasible.
However, when it comes to specific drugs, the right drug at the right time for the right patient does and should depend on evidence and that evidence needs to be generated through clinical trials, and not depend on opinion. Many of the early Chinese clinical trials failed to meet their recruitment targets and initially we had little evidence to base our recommendations on.
To know what drugs are needed when, it is important to understand how the disease is caused and develops. In the early phase, the disease is primarily driven by replication of Sars-CoV-2. Later, and especially when the infection is not controlled and symptoms start to become severe, the disease appears to be driven by an uncontrolled immune and inflammatory response to Sars-CoV-2 that leads to tissue damage. Based on this understanding, in general, any antiviral treatment would have the greatest effect early in the course of the disease, while immunosuppressive/antiinflammatory therapies would be needed in the later stages of Covid-19.
With positive data on budesonide (an inhaled steroid used for asthma) in early illness and dexamethasone in hospitalised patients with severe disease from the Stoic and Recovery trials, it appears that steroids are important to stop the disease from progressing. Many drugs for which there was some hope, such as the antiviral lopinavir/ritonavir, interferon and hydroxychloroquine have been shown not to work.
For remdesivir, the Solidarity trial showed no effect on severe disease or death, but the ACTT-1 trial showed that for patients who were at the stage of requiring supplemental oxygen, but not yet needing high-flow oxygen or non-invasive ventilation, remdesivir provided some benefit in shortening duration and preventing death. This highlights that the drug is not for every patient, but for a small subset at a specific stage of treatment.
Similarly, for tocilizumab, evidence-based recommendations are narrow, for a subset of patients with rapid progression who need either high-flow oxygen or non-invasive ventilation, and in combination with other therapy including steroids. For plasma therapy, there is no evidence that any plasma from any group of donors is helpful as shown in the Indian Council of Medical Researchsupported Placid trial, and is not currently recommended. Clear answers come from large clinical trials. We have over 400 registered studies in the Clinical Trials Registry of India, mostly small studies that will not inform future practice.
As people desperately seek drugs that may not be needed, we have an ethical and moral responsibility to ensure that all health care providers use evidence to inform treatment. Professional organisations, clinical research communities, the regulator and policymakers must play a role in ensuring that treatments are used according to need and not to create false hope.