Molnupiravir treatment fails to reduce adverse outcomes among high-risk vaccinated patients

11th January 2023

Molnupiravir treatment failed to reduce both COVID-related hospitalisation and mortality among high-risk vaccinated adults in the community

Molnupiravir treatment in vaccinated, high-risk patients infected with COVID-19, failed to reduce both the rate of hospitalisation and death compared to usual care according to the results of a large, randomised trial by members of the PANORAMIC Trial collaborative group.

It is possible that the early treatment of COVID-19 infected patients with anti-viral agents, might prevent deterioration, speed up recovery and reduce the need for hospital admission. One such anti-viral is molnupiravir (EIDD-2801) and which was originally shown to be a potentially effective clinical candidate with high potential for monotherapy of seasonal and pandemic influenza virus infections.

Nevertheless, early molnupiravir treatment in patients infected with COVID-19 and at least one risk factor for severe illness, was subsequently shown to reduce the risk of hospitalisation or death in unvaccinated adults. But with millions of individuals now vaccinated against COVID-19, it remains uncertain whether molnupiravir treatment is still an effective option in such patients.

There is some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this is not conclusive. As a result, in the present study, researchers set out to establish the effectiveness of molnupiravir in vaccinated, high-risk, community patients at reducing hospital admission or death.

The study included community (i.e., non-hospitalised) patients aged 50 years and older, or 18 years and older with relevant comorbidities and who had COVID-19 symptoms within the previous 5 days, together with a positive PCR or rapid antigen test within the past 7 days. Eligible participants were randomly assigned (1:1) to receive molnupiravir 800 mg twice daily for 5 days plus usual care or usual care alone. The primary outcome was set as all-cause hospitalisation or death within 28 days of randomisation.

Molnupiravir treatment and adverse COVID-19 outcomes

A total of 25,783 individuals with a mean age of 56·6 years (58.5% female) were randomised to molnupiravir (12, 821) or usual care. Additionally, 69% of the whole cohort had comorbidities and 94% had received at least three doses of a COVID-19 vaccine.

Hospitalisations or deaths were recorded in 1% of both groups (adjusted odds ratio, aOR = 1·06, 95% CI 0·81 – 1·41, p = 0.33). Moreover, in subgroup analyses, there were no significant differences when assessed on several factors including the presence/absence of co-morbidities, age (< 65 vs > 65), or among those who were immunocompromised.

Despite no difference in the primary outcome, molnupiravir treatment was associated with a reduction in the median time from randomisation to first recovery (hazard ratio, HR = 1·36, 95% CI 1·32 – 1·40).

The authors concluded that in a highly vaccinated population at high risk of complications from COVID-19, the avoidance of hospitalisation and death was primarily achieved via extensive vaccination. They added that the benefits of molnupiravir in terms of a faster recovery time need to be considered in the context of several other relevant factors including the prevailing disease, burden on health-care services, drug-acquisition cost, social circumstances, cost-effectiveness, and opportunity costs.

Citation
Butler CC et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet 2022.

Meta-analysis finds PCSK9 inhibitors and ezetimibe combined with statins reduce non-fatal MI and stroke in high risk patients but not death

20th May 2022

PCSK9 inhibitors and ezetimibe added to statins in high-risk cardiovascular disease patients reduces non-fatal MIs/stroke but not mortality, study shows

Adding PCSK9 inhibitors and ezetimibe to maximally tolerated statin therapy in patients at a high risk of a cardiovascular event reduces the risk of a non-fatal myocardial infarction (MI) and non-fatal stroke but does not significantly reduce either all-cause mortality or cardiovascular mortality.

This was the main finding from a network meta-analysis of trials by a group of US and Chinese researchers.

The 2021 European Society of Cardiology guidelines on cardiovascular disease prevention in clinical practice recommend that a high-intensity statin is prescribed up to the highest dose that can be tolerated in order to reach the LDL target for a specific risk group.

Furthermore, the joint American College of Cardiology/American Heart Association Task Force has suggested that in patients at very high cardiovascular risk and whose LDL-C level remains ≥70mg/dl (≥1.8mmol/l) on maximally tolerated statin and ezetimibe therapy, adding a PCSK9 inhibitor is a reasonable option.

Previously published data has already shown that when added to statin therapy, ezetimibe produces an incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Similarly, addition of alirocumab (a PCSK9 inhibitor) to patients receiving high-intensity statin therapy, reduced the risk of recurrent ischaemic cardiovascular events. 

Whilst the benefits of both treatments cholesterol lowering agents are clear, the benefits to an individual patient depends upon their baseline risk. Moreover, the absolute incremental benefit derived from combining PCSK9 inhibitors and ezetimibe either separately or in combination, among individuals taking a maximally tolerated dose of statin or for those who are statin-intolerant and with different levels of baseline cardiovascular risk, remains to be determined.

For the present study, the authors performed a network meta-analysis of randomised controlled trials in which patients had a median baseline LDL cholesterol value > 1.8mmol/l and where they were randomised to receive PCSK9 inhibitors vs control, ezetimibe vs control, or PCSK9 inhibitors vs ezetimibe.

The researchers assessed the relative and absolute risks (per 1000 patients treated for 5 years) in terms of non-fatal MI, non-fatal stroke, all-cause mortality and cardiovascular mortality. Patients were also categorised as being at low to very high cardiovascular risk.

The authors set the minimal important difference as 12 per 1000 reductions for non-fatal MI, 10 per 10,000 for a non-fatal stroke and 8 per 1000 for all-cause or cardiovascular mortality.

PCSK9 inhibitors and ezetimibe and cardiovascular outcomes

A total of 16 trials with 111,098 patients (median age 61 years) and a median LDL cholesterol concentration of 2.71mmol/l, were followed-up for a median of 2 years and included in the analysis.

Among patients prescribed statins, addition of a PCSK9 inhibitor reduced the risk of a non-fatal MI by 19% (relative risk, RR = 0.81, 95% CI 0.76 – 0.87), non-fatal stroke by 26% (RR = 0.74) but not all-cause mortality (RR = 0.95, 95% CI 0.87 – 1.03) or cardiovascular mortality (RR = 0.95, 95% CI 0.87 – 1.03).

Similarly, the addition of ezetimibe reduced non-fatal MI and non-fatal stroke by 13% and 18% respectively but, again, there was no significant effect on all-cause or cardiovascular mortality.

Among adults with a very high cardiovascular risk, the authors calculated that adding a PCSK9 inhibitor to statins would lead to 16 fewer non-fatal MIs and 21 non-fatal strokes. Adding ezetimibe to a similar or equivalent statin patient, would lead to 14 fewer non-fatal strokes and 11 fewer MIs.

Finally, adding PCSK9 inhibitors and ezetimibe to a statin would reduce non fatal strokes by 14 per 1000 and stroke by 17 per 1000, although there was no impact on all-cause or cardiovascular mortality.

The authors also found that among patients with low to moderate risk of cardiovascular disease, adding either a PCSK9 inhibitor provided no additional benefit over statin therapy alone. In other words, it was only patients with the highest cardiovascular risk who benefited from adding either ezetimibe or a PCSK9 inhibitor to their statin.

Similar reductions, again only among high or very high risk individuals and a lack of mortality benefit, were observed in patients intolerant of statins.

The authors concluded that the benefits of adding PCSK9 inhibitors and ezetimibe were limited largely to patients only with a high or very high cardiovascular risk.

Citation
Khan SU et al. PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis BMJ 2022