Trials and Expiration Dates

Three examples of previously beneficial treatments that need to be retested because the clinical situation changed

Randomized clinical trials are the best way to know what works in medicine. While medical interventions (drugs or devices) remain the same, situations often change.

One of the cool things that our Cardiology Trials substack project (Andrew Foy and Mohammad Ruzieh and I are cataloging the seminal trials) is teaching me, is that medications/devices proven effective in trials decades ago, may no longer have benefit now.

Beta-blockers after heart attack for instance. The BHAT trial established oral propanolol given 14 days after an MI as effective.

In the 1980s, however, MIs were a lot different than now. Now, interventional cardiologists stop most heart attacks by opening the clotted off artery—which prevents heart damage. In the 1980s, heart attacks caused substantial heart injury, and the beta-blocker helped mitigate some of the ill effects from that injury.

While beta-blockers after MI remain a standard of care, many investigators are re-doing trials to test beta-blocker utility in this era. These will likely show that the once helpful drugs no longer help.

Beta-blockers have not changed. Their chemical structure is the same. What changed is the clinical situation.

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The implantable cardioverter defibrillator (ICD) is another example. Around the turn of the century, two big trials found that ICD implantation in patients with heart failure reduced the risk of dying compared to medication alone.

ICDs provided this benefit because many patients with heart failure die from a sudden arrhythmia. ICDs prevent this kind of death by delivering a shock to stop cardiac arrest. ICDs, rightly, became a standard preventive procedure.

But things have changed. Heart failure therapy has improved greatly. Trialists have reported declining rates of sudden arrhythmic death in patients with heart failure.

This explains why the latest ICD trial, called DANISH, found absolutely no benefit from an ICD in patients with heart failure.

The changing milieu of heart failure (less arrhythmia and better background therapy) explains why a German team are now repeating one of the seminal trials of ICD therapy.

It’s called the PROFID EHRA trial and it will essentially mirror the old seminal trials. If PROFID is non-significant, like DANISH, the once beneficial ICD will no longer be beneficial.

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Nirmatrelvir (plus ritonavir) or Paxlovid for the treatment of infection due to SARS-CoV2 follows a similar path of changing clinical milieu.

The EPIC-HR trial of N/R vs placebo found a marked reduction in the primary endpoint of infection-related hospitalization or death. These were high-risk unvaccinated patients.

Nothing has changed with the drug; its chemical structure remains.

What has changed is the clinical situation. The company has now posted results of the EPIC-SR trial. The same drug vs placebo—but a year later. In EPIC-SR, the same drug had no significant effects.

The negative results of EPIC SR can be explained in the same way as the ICD story. SARS-CoV2 infection has changed—for the better. The virus mutated to less virulent forms. More people have have immunity through previous infection or vaccination.

There still could be high-risk patients with viral infection who benefit from N/R, but now the onus is on proponents to do another trial. Just as being done for beta-blockers and ICDs.

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The message for those interested in critical appraisal of evidence is to stop and think about the clinical situation studied during the trial vs the current situation.

Interventions once proven effective may no longer be so in a new environment.