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The TIOSPIR trial was used to support safety of the mist inhaler version of tiotropium (Spiriva) compared with the dry powder version, but the pooled data actually showed something else -- a worrying signal for heart attack risk, researchers argued.

Adjudicated among chronic obstructive pulmonary disease (COPD) patients on either dose of the tiotropium Respimat Soft Mist inhaler than among those using the dry powder HandiHaler (P=0.04), , of England's University of East Anglia, and colleagues found.

Fatal or nonfatal MIs showed a 37% elevated risk with Respimat versus HandiHaler, although the results were of borderline statistical significance at P=0.05, the investigators said in their analysis of the published data.

"Our findings cast serious doubt on assertions (in the article and the accompanying editorial by Jenkins) regarding the perceived cardiac safety of tiotropium Respimat," they wrote in a letter to the New England Journal of Medicine.

The trial had been done to settle questions about , which had been raised by a 2011 meta-analysis by Loke's group and (Boehringer Ingelheim and Pfizer).

TIOSPIR randomized 17,135 COPD patients to double-blind treatment with tiotropium Respimat (2.5 or 5 mcg once daily) or tiotropium HandiHaler (18 mcg once daily).

It showed noninferiority on all-cause mortality risk for both Respimat dose groups versus HandiHaler, and no differences in either composite major cardiovascular adverse events or in deaths among patients with a history of cardiac arrhythmia.

But those results don't bring an end to the debate, Loke's group maintained. "We believe that focusing on overall mortality or composite cardiovascular end points may mask differences in cause-specific mortality, such as from myocardial infarction," they wrote.

In support of a real effect, they pointed to higher relative risk at the 5-mcg Respimat dose than at the 2.5-mcg dose for both fatal MI and the combination of fatal and nonfatal MI, "raising the possibility of a dose-response relationship."

Also, prior observational data from a large Dutch general practice research database supported that risk, showing that the increased risk of death with Respimat versus HandiHaler was highest related to cardiovascular or cerebrovascular death (adjusted hazard ratio 1.56, 95% confidence interval 1.08-2.25).

The TIOSPIR researchers responded that the MI findings may have been a spurious association from multiple comparisons in the trial, and that they weren't contributing to any excess in overall mortality or in cardiac events.

"Accordingly, we see no reason to conclude that one delivery device for tiotropium is less safe than the other or bears a greater risk of major adverse cardiovascular events," they concluded.

However, the editorialist on the original TIOSPIR paper wasn't so quick to dismiss the risk. The issue warrants further study because, "given its gravity, this is an important outcome," , of the University of Sydney, wrote in a response letter.

She suggested post-marketing surveillance focused on MI.

"By no means should these findings be ignored," COPD expert , of the University of Nebraska Medical Center in Omaha, commented in an interview with 番茄社区. "I'm not sure the debate on safety is ever closed ... for any medication, no matter how long it has been around."

But he also suggested it likely wasn't a clinically important safety risk because MI accounted for a relatively small proportion of deaths in the trial (just 10 in the 2.5-mcg Respimat group and 11 in the 5-mcg group versus three on HandiHaler, out of more than 400 total deaths in each group during the trial).

One possible explanation for the 27% elevated mortality risk found in the Dutch real-world study was chronic kidney disease, Katia Verhamme, MD, PhD, of Erasmus Medical Center in Rotterdam, the Netherlands, and colleagues noted in another letter to the NEJM.

When looking only at people with normal kidney function, the real-world mortality results agreed with those of TIOSPIR, which excluded individuals with moderate-to-severe renal impairment.

But when looking at those with stage 3 to 5 chronic kidney disease, the adjusted hazard ratio for death from any cause was 1.52 with Respimat versus HandiHaler (95% CI 1.02-2.28).

"Tiotropium is excreted by the kidneys, and the prescribing information for tiotropium states that patients with impaired renal function should be monitored closely," , of Johns Hopkins, responded on behalf of the TIOSPIR group. "Thus, we endorse monitoring patients with impaired renal function for adverse anti-cholinergic effects, regardless of the delivery device."

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