Paxlovid doesn’t work. Surprise?

Despite incredibly underwhelming evidence from the outset, a massive amount of money was spent (or wasted) on Paxlovid during the COVID pandemic. Some of the issues are endemic to medical science. When we allow companies to test their own products with billions of dollars on the line, the results are horrendously biased from the outset. Unfortunately, despite incredibly weak and biased data, Paxlovid (among many other COVID therapeutics) was pushed forward using the incredibly flawed logic that we should lower our scientific standards during a pandemic. Now, years later, when Pfizer has already made its billions, and no one cares or is prescribing Paxlovid any more, we finally get some high quality independent data, and the results are just what you would expect.

The question

Does nirmatrelvir–ritonavir (Paxlovid) reduce the incidence of hospitalization or death among vaccinated higher-risk participants with SARS-CoV-2 infection?

The paper

Butler CC, Pinto AD, Harris V, Holmes J, Rahman NM, Cureton L, Hayward G, Richards DB, Lowe DM, Standing JF, Breuer J, Hood K, Png ME, Petrou S, Dorward J, Patel MG, Thomas NPB, Evans P, Hart ND, Jani BD, Hosseini B, Murthy S, McBrien K, Condon A, McDonald EG, Daley P, Greiver M, da Costa BR, Selby P, Jüni P, Lee TC, Shi H, Detry MA, Saunders CT, Fitzgerald M, Berry NS, Saville BR, Khoo SH, Nguyen-Van-Tam JS, Hobbs FDR, Yu LM, Little P; PANORAMIC Trial and CanTreatCOVID Trial Collaborative Groups. Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients. N Engl J Med. 2026 Apr 23;394(16):1583-1594. doi: 10.1056/NEJMoa2502457. PMID: 42019019

The methods

This publication actually covers 2 separate trials:

PANORAMIC was a national, multicenter, open-label adaptive clinical trial based out of 65 general practice hubs in the United Kingdom.

CanTreatCOVID was a national, multicenter, primary care, open-label adaptive clinical trial based out of Canada.

Patients

Higher-risk adults (≥50 years of age or ≥18 years of age with relevant coexisting conditions) in the community who had had symptoms of SARS-CoV-2 infection for 5 days or less and had a positive polymerase-chain-reaction or rapid antigen SARS-CoV-2 test.

Intervention

Paxlovid (nirmatrelvir 300 mg plus ritonavir 100 mg) twice daily for 5 day, in addition to usual care.

Comparison

Usual care alone. 

Outcome

The primary outcome was nonelective hospital admission for any cause or death from any cause within 28 days after randomization.

The results

PANORAMIC

They included 3516 patients in this part of the trial, although 25,779 were randomized to other therapies, and 126,421 were screened. The adaptive multi-therapy aspect of the trial makes it a lot harder to assess the potential of selection bias. The mean age was 55, 70% were female, median length of symptoms was 3 days, and 98% had 2 or more COVID vaccinations. 8 patients (0.5%) in the usual care group were prescribed paxlovid outside of the context of the trial.

There was no difference in the primary outcome of hospitalization or death, which occurred in 0.8% of the paxlovid group and 0.7% of the usual care group.

“Early sustained recovery”, defined as symptom improvement by 14 days, was better with paxlovid (33% vs 22%), although I wouldn’t consider 14 days early recovery. 

Adverse events occurred in 96% of the paxlovid group! For some reason they don’t report a number in the usual care group, which seems odd. Serious adverse events were only about 1%. 

CanTreatCOVID

721 patients were randomized out of 1997 screened. The mean age was 55, 66% were female, median length of symptoms was 2 days, and 98% had 2 or more COVID vaccines. 11 patients (3%) in the usual care group were prescribed paxlovid outside of the context of the trial. 

There was no difference in the primary outcome of hospitalization or death, which occurred in 0.6% of the paxlovid group and 1.2% of the usual care group.

“Early sustained recovery”, defined as symptom improvement by 14 days, was again better with paxlovid (69% vs 53%). 

Adverse events were much higher with paxlovid (36% vs 6%), although the trend was flipped for serious adverse events (1% vs 3%). 

My thoughts

As I said at the outset, I am not surprised by the results. I think we rushed the use of Paxlovid in the first place, and have never been convinced there was real benefit. EPIC-HR was a statistically positive trial, but when you combined the low pretest probability that we were going to find the first antiviral effective in respiratory viral infections with the many methodology problems and the fact that trial has run entirely by Pfizer, I did not think the results were strong enough to warrant widespread use of the drug. (Hammond 2022) However, the 1.3% mortality benefit definitely seemed important enough to warrant follow-up, independent research. Despite being completed at the same time, Pfizer sat on the results of the negative EPIC-SR for a full 2 years, presumably to drive up sales before tempering enthusiasm for Paxlovid. (Hammond 2024) It is nice to see some independent data, but at this point I think it is too late: Pfizer ran away with their bags full of cash, and basically no one is prescribing Paxlovid anymore. (Although, much like Tamiflu, I still see a large number of patients presenting with clear medication side effects after being prescribed these drugs from walk-in clinics, so I guess there are still some believers out there.)

Both of these trials were negative for their primary outcome, and I believe that is the result that will be most consistent with reality, but these trials don’t definitively prove that Paxlovid provides zero benefit.

Both trials ended up significantly under powered. Both trials are smaller than their calculated sample size. The Canadian trial just stopped because of slow recruitment. The UK trial realized that the incidence of the primary outcome was significantly lower than expected, ran a new sample size calculation, and somehow decided that despite the fact that they were seeing far fewer events, they actually needed a much smaller study (decreasing from their original plan of 10,600 patients all the way to 2,876.) I don’t follow their logic, but it does mean that the trial is going to be underpowered for small but real differences between the groups. In an under powered trial, I suppose the 0.6% difference seen in the Canadian trial might be clinically important.

Of course, I don’t know exactly what that 0.6% means. When you use a composite outcome as your primary outcome, it is essential that you present the data on the components on the composite. For some reason, they don’t do that here. They don’t present the data individually for death or hospitalization, only the combined number, which seems like a big editorial failure. 

There are also the positive secondary outcomes, which some people will talk about. Of course, positive secondary outcomes in trials with negative primary outcomes are at best hypothesis generating, and will turn out to be wrong way more often than they are right. Also, the outcomes are just weird. First of all, 14 days is not early recovery. Second of all, how were 80% of the usual care patients still symptomatic at 14 days in the UK trial? Even the 50% in the Canadian trial seems way too high to me. I don’t know exactly what this is measuring. However, when you factor in the adverse event rates, it doesn’t seem like there could be a net benefit in overall symptoms. More importantly, these were unblinded trials looking at self reported symptoms, so I think the outcome should be mostly ignored in favor of the more objective primary outcome. 

Unlike a lot of the trials we saw during the pandemic, these trials used all cause hospitalization or death as their outcome. This came up time and again during the pandemic, because trials kept using the inherently biased “COVID-related hospitalization” rather than just “hospitalizatoin”,. It was nice to see better methodology here. That being said, the Canadian study only got this information based on patient self report, and so accuracy is questionable. (If a patient was held overnight in the emergency department for a next day ultrasound completely unrelated to COVID, are they reporting that as a night spent in the hospital or not?)

People will probably make a big deal about changes in the population over time – the idea being that unvaccinated or previously unexposed patients were way higher risk, but that population doesn’t exist any more. Although that could be true, I think the much simpler explanation as to why Paxlovid doesn’t work in these two trials is that it never worked. My take on the initial research was that this drug probably did nothing, especially when you factored in the significant conflicts of interest. If all you care about is this single clinical decision, this distinction doesn’t matter. The answer is clear. No one should be using Paxlovid in 2026. However, I think it would be a mistake to whitewash the scientific mistakes made during the pandemic with retrospectively fit explanations based around shifting population risks. We do this over and over again in medicine. We rush to new therapies based on very low quality evidence, and then act shocked when high quality research demonstrates what was pretty obvious all along. (Think about therapeutic hypothermia, for example.)

Bottom line

These two open-label RCTs show no benefit from Paxlovid in preventing death or hospitalization when used in higher risk out patients with COVID-19. I see little to no reason for Paxlovid to be used in emergency department patients. 

Other FOAMed

Paxlovid:

Paxlovid doesn’t work for long COVID either (The STOP-PASC trial)

EPIC-HR: Some underwhelming data on Paxlovid

EPIC-SR: The negative paxlovid data Pfizer has been sitting on

Paxlovid evidence: still very little reason to prescribe

EBM:

Evidence based medicine is easy

The EBM bibliography

Evidence based medicine resources

EBM deep dives

References

Butler CC, Pinto AD, Harris V, Holmes J, Rahman NM, Cureton L, Hayward G, Richards DB, Lowe DM, Standing JF, Breuer J, Hood K, Png ME, Petrou S, Dorward J, Patel MG, Thomas NPB, Evans P, Hart ND, Jani BD, Hosseini B, Murthy S, McBrien K, Condon A, McDonald EG, Daley P, Greiver M, da Costa BR, Selby P, Jüni P, Lee TC, Shi H, Detry MA, Saunders CT, Fitzgerald M, Berry NS, Saville BR, Khoo SH, Nguyen-Van-Tam JS, Hobbs FDR, Yu LM, Little P; PANORAMIC Trial and CanTreatCOVID Trial Collaborative Groups. Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients. N Engl J Med. 2026 Apr 23;394(16):1583-1594. doi: 10.1056/NEJMoa2502457. PMID: 42019019

Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, Baniecki M, Hendrick VM, Damle B, Simón-Campos A, Pypstra R, Rusnak JM; EPIC-HR Investigators. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022 Feb 16:NEJMoa2118542. doi: 10.1056/NEJMoa2118542. Epub ahead of print. PMID: 35172054  

Hammond J, Fountaine RJ, Yunis C, Fleishaker D, Almas M, Bao W, Wisemandle W, Baniecki ML, Hendrick VM, Kalfov V, Simón-Campos JA, Pypstra R, Rusnak JM. Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19. N Engl J Med. 2024 Apr 4;390(13):1186-1195. doi: 10.1056/NEJMoa2309003. PMID: 38598573