Positively Negative

Charlie Plain | June 9, 2014

The world loves to hear about research breakthroughs that trounce disease or save lives. But what about negative findings that show treatments or drugs don’t work? Can they be considered positive news, too?

An x-ray of COPD-damaged lungs. Credit: James Heilman, MD

In a prime example, earlier this month Temple University and the National Heart, Lung and Blood Institute jointly announced that a study failed to show any benefits in using statin drugs to treat flare-ups of COPD. COPD, or chronic obstructive pulmonary disease, is the third leading cause of death in the United States.

Previous studies had indicated that statins might offer a benefit for COPD treatment and the medical community was optimistic that they might be the game changer for this incurable disease.

“Statins have some anti-inflammatory effects and COPD is basically an inflammatory disease resulting from years of smoking or other kinds of exposures that damage the lungs,” says School of Public Health professor John Connett. “The idea was that statins would relieve the inflammation and reduce the frequency of the exacerbations, or flare-ups.”

Temple University’s Gerard Criner headed up the study and collaborated with Connett and other investigators in the United States and Canada. Connett filled the critical role of lead biostatistician and advised Criner on the study’s design to make sure the science was rock solid and the data yielded results that could truly answer whether or not statins help with COPD.

By its conclusion, Connett had crafted and conducted a study that was so convincing of the drug’s failure that it garnered the highest scientific attention and its results proved to be, in a sense, “positively negative.”

Directing data

Connett has a long track record directing studies, including the seminal Lung Health Study, which was the largest COPD study ever conducted and involved 5,887 participants.

“Basically, it showed it’s a very good idea to quit smoking. You will probably live longer,” says Connett.

For the new investigation, Connett devised a study that would last up to four years and span  45 clinics in the United States and Canada. He and his team of statisticians and data managers based the study’s data coordination center inside SPH’s Division of Biostatistics and built an online submission system for collecting patient information and test results.

At full cry, the center was tracking 885 people who were generating thousands of data records and blood samples for approximately two years.

But then at the study’s peak of operation, the study’s Data and Safety Monitoring Board (DSMB) called a halt.

Negative, but helpful

Routine monitoring of the patient’s test results showed that statins were doing absolutely nothing to curb COPD exacerbations.

“We stopped the study because of what’s called ‘futility,’ says Connett. “We had ruled out any large beneficial or harmful effect from statins.”

It was a dead-end discovery and major journals, which tend to favor breakthrough declarations, seemed destined to ignore any paper about the study.

But much to everyone’s surprise, both the New England Journal of Medicine (NEJM) and JAMA expressed serious interest in a paper. The team chose NEJM, though the journal gave them only eight weeks to submit it.

“Somehow we got it done,” says Connett.

One of the main reasons the paper came together so well and so quickly is that Connett insisted on getting a last clinic visit from all participants even after the study ended, an unusual request. The final data strongly confirmed the DSMB’s decision regarding the current health of the subjects and that allowed Connett to produce detailed and convincing evidence of statins’ ineffectiveness for treating COPD.

So while the results of the study dashed the hopes of physicians who treat COPD and people who have the disease, Connett still considers the negative outcome to be helpful. He believes so because clearly ruling out the use of statins helps researchers narrow down the list of possibilities for treating COPD and provides direction for further investigation.

“We’re going to be working on more studies and analyzing data on biomarkers that we collected from this one to see if they have something to do with triggering exacerbations and other illnesses COPD patients have,” says Connett. “I’d love to eventually find something that turns out to be truly positive.”

~ Post by Charlie Plain

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