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• Two common antiretroviral drugs given to Covid-19 patients can cause bradycardia, a serious slowing of the heart
• These drugs had been considered a promising treatment for Covid -19
• Going forward, the experimental antiviral drug remdesivir appears to be a much more effective alternative 

Older, critically ill Covid-19 patients who are given a combination of two common antiretroviral drugs can experience a drastic slowing of their heart rate, French researchers report.

In their study of 41 patients treated with lopinavir and ritonavir twice daily for 10 days, 22% developed a slow heart rate condition called bradycardia. When the drugs were stopped or doses lowered, the patients’ heart rates returned to normal, according to the team from Amiens University Hospital, in France.

“There are extensive investigations underway to find therapies that are effective at treating patients infected with Covid-19,” said Dr Gregg Fonarow, a professor of cardiology at the University of California, Los Angeles, who had no part in the study.

Potential for bradycardia

The lopinavir-ritonavir combo had been considered a promising treatment for Covid-19 based on very small reports, randomised clinical trials and off-label use, Fonarow said.

But earlier studies have suggested that this combination may also lead to heart block, a problem with electrical signals in the heart. “Determining how these drugs lead to the bradycardia will require further study,” Fonarow said.

Doctors prescribing these drugs should be aware of the potential for bradycardia and carefully monitor patients, he added.

“Moreover, preliminary clinical trial results suggest this therapy is not effective in Covid-19, so use in this setting will likely be very limited going forward,” Fonarow said.

Lopinavir and ritonavir have also been used to treat other viruses, including SARS (severe acute respiratory syndrome), MERS (Middle East respiratory syndrome) and HIV. The researchers noted that bradycardia has also been seen among HIV patients treated with the drugs.

Normally, adults’ hearts beat between 60 and 100 times a minute. In bradycardia, the rate falls below 60 beats per minute, causing decreased blood flow that can lead to fainting, chest pain, low blood pressure and heart failure.

Combo not well tolerated

Patients in the French study who developed the problem were older than ones who did not, averaging 62 to 80 years of age, the researchers reported.

Dr Marc Siegel, a professor of medicine at NYU Langone Medical Center in New York City who reviewed the findings, noted that the two-drug combo had not helped hospitalised Covid-19 patients in other recent trials.

Siegel said the treatment should not be used with Covid-19 because it’s not effective in either critically ill patients or in the early stages of the disease.

“The remaining hope for this combination of drugs was early in the disease, but the significant amount of bradycardia in these critically ill patients raises the question that this combo is not well tolerated in many patients,” he said.

Going forward, Siegel said, the experimental antiviral drug remdesivir appears to be effective and is already being used to fight Covid-19.

The new study, by Dr Christophe Beyls and colleagues, was published early in 9 July  in the journal Circulation: Arrhythmia and Electrophysiology.

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• Many Covid-19 patients present with blood clots that can be deadly
• These blood clots are linked to the endothelial cells that line the inside of blood vessels 
• Researchers are trying to find strategies to safeguard the endothelial layer and prevent blood clots from forming

Covid-19 is linked to potentially fatal blood clots. Researchers now believe they’ve found out how they occur, which potentially could lead to better treatment.

“While many forms of illness can generate blood clots, the endothelial cells that line the inside of blood vessels play a surprisingly large role in Covid-19 clotting,” said researcher Dr Alfred Lee, an associate professor of medicine at Yale Cancer Center.

“Endothelial damage is a central component in the entire spectrum of Covid-19 disease. Our study is the first to demonstrate that this process of endothelial damage is present in a wide range of Covid-19 patients, particularly as people become critically ill,” Lee said in a Yale news release.

For the study, Lee and his team examined the blood of 68 patients with Covid-19. Of these patients, 48 were critically ill in an ICU. The other 20 were hospitalised but not in the ICU.

Therapeutic strategies

The researchers found that some markers of endothelial cell and blood platelet activation were nearly twice as high in the ICU patients compared to those not in the ICU.

One marker, called thrombomodulin, was linked with survival among all patients. Measuring thrombomodulin might help doctors better treat patients, the researchers say.

“If we have a marker to identify which patients are most likely to progress towards critical illness and possibly death, that would be hugely helpful, as these patients might benefit from closer monitoring and possibly earlier intervention,” Lee said.

Study co-author Dr Hyung Chun is trying to develop a test based on thrombomodulin, which is elevated in other life-threatening diseases as well.

“The other goal we’re pursuing in parallel is to find therapeutic strategies that could safeguard the endothelial layer and may prevent the blood clots from forming,” said Chun, an associate professor of medicine and pathology at Yale School of Medicine. “Are there approved drugs we could potentially repurpose for this context?”

One possible candidate is the drug dipyridamole, used to prevent stroke.

The report was published late in June in the journal The Lancet Haematology.

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