A new study suggests Americans with heart failure may benefit less from recommended medications than patients in other countries.

The findings, which one doctor called "provocative," point to an emerging problem in drug development: As research becomes increasingly international, the outcomes may be less dependable in individual countries.

In the new work, researchers drive that point home for drugs known as beta blockers, which gold-standard tests have shown can extend the life of people with heart failure.

Breaking those drug trials down by country, it turns out U.S. patients didn't benefit appreciably, whereas the number of deaths during the trials fell by more than five in 100 in the rest of the world.

Lead researcher Dr. Christopher O'Connor, a cardiologist at Duke University Medical Center in Durham, North Carolina, said earlier studies had hinted of geographical differences in outcomes, but never as clearly as the new results.

Some five million Americans are living with heart failure, in which the heart fails to pump enough blood into the body. The condition is involved in about 300,000 deaths every year, according to the National Institutes of Health.

O'Connor's study, released Monday in the Journal of the American College of Cardiology, represents the first sweeping look at how beta blocker trials may come to different conclusions depending on the nationality of the participants.

He and his colleagues pooled results from so-called randomized controlled trials — the strongest experimental design available to doctors — that included U.S. patients.

They found four trials — the MERIT-HF, the COPERNICUS, the CIBIS-2, and the BEST trials — with a total of some 9,000 participants, nearly half of them American.

During those studies, beta blockers cut deaths among non-U.S. patients by 36 percent, while there was no statistically reliable drop among U.S. patients.

While that doesn't necessarily mean Americans don't benefit at all, it does question heart failure treatment guidelines, which often rely on international trials.

"It raises some concerns," O'Connor told Reuters Health. "If the patients have these differential treatment effects, we have to pay attention to it."

There aren't any clear-cut answers to why the outcomes vary by country.

It could be a question of different use of medications or devices to control heart failure, or it could be a chance finding because only one study included a large proportion of U.S. patients, the researchers write.

O'Connor said genetic differences might also be at play, because African Americans more often harbor a gene variant that makes them less responsive to beta blockers than whites. His study was funded in part by ARCA biopharma, which is developing a genetically targeted beta blocker treatment.

Whatever the explanation for the geographical variation, it's a problem drug developers would do well to tackle if they want their products to be approved by the U.S. Food and Drug Administration, according to O'Connor.

"This really goes beyond the beta blocker and heart failure story, it's about how we conduct clinical trials," he said. "I think the FDA gets nervous when they keep seeing these trends where, things may not look as good in the U.S."

As a case in point, for a while it appeared the FDA might not approve drugmaker AstraZeneca's new blood thinner Brilinta, because North American patients taking the drug did worse than patients on an older blood thinner -- which wasn't the case for European patients in the study.

AstraZeneca finally convinced the FDA the reason for the poorer results in North America might be related to the fact that aspirin interferes with Brilinta, and aspirin is more commonly used by heart patients in the U.S. than in Europe. The FDA approved Brilinta on July 21.

In an editorial in the same journal, Dr. Barry M. Massie, explains that many drug trials have now become "megatrials," including several thousand patients in different countries.

That's partly because current drugs and medical devices are so effective now that most advantages from new treatments will be miniscule. As a result, it requires lots of patients to show that potential benefits aren't just a result of chance.

While Massie, of the VA Medical Center in San Francisco, calls the new findings "provocative," he adds that American patients might still benefit from beta blockers.

"Most important, one cannot exclude the play of chance in these findings," he writes.