Grasping at Straws while Gasping for Air

The phone call came in early October, 2011. “You could sense the tone of it right away,” recalls pulmonologist Imre Noth, MD, who runs one of the country’s largest practices for patients with pulmonary fibrosis. “There was just something about the voice on the line.”

The conference call came from the data and safety monitoring board for PANTHER-IPF, a multi-center, placebo-controlled clinical trial designed to evaluate the merits of three-drug therapy to treat idiopathic pulmonary fibrosis. The combination had long been in use, but never so rigorously tested. An earlier trial had found that the three drugs – azathioprine, prednisone and N-acetylcysteine – might be better than two drugs, azathioprine and prednisone, but the result was unconvincing and the matter remained controversial. PANTHER was launched to settle the issue. It did so in half the allotted time.

“After the planned midpoint interim analysis,” the study directors noted in their New England Journal of Medicine article, “the data and safety monitoring board recommended discontinuation of the three-drug regimen because of an excess of deaths, hospitalizations and serious adverse events among patients in the combination-therapy group, as compared to the placebo group.”

Patients getting all three drugs were eight times as likely to die as those getting placebo. On October 14, the study sponsor instructed the investigators to stop the three-drug regimen “effective immediately.”

At about the same time, the data safety monitoring board for a different study Noth was running — ACE-IPF, for Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis — hit the same roadblock. Warfarin, a common anticoagulant, did not appear to provide any benefit and more than four times as many people who were taking the drug died as those who received a placebo. That trial also stopped at the midpoint.

Pulmonary fibrosis was already a difficult disease with few treatment options, “except for lung transplant, none of them terribly appealing,” said Noth, associate professor of medicine director of the interstitial lung disease program at the University of Chicago Medicine. “I got a lot of phone calls, doctors from all over the country. They all began: ‘Now what do I do?’”

The papers describing the results from both trials are painfully similar. “Idiopathic pulmonary fibrosis is a chronic, progressive disease of unknown cause,” they both begin. The median survival of patients after diagnosis is two to five years. The ACE paper adds: “To date, no pharmacologic therapies have definitively been shown to improve survival.”

Both treatment approaches made some sense. The PANTHER trial was banking on immunosuppression helping patients with a disease often associated with inflammation. ACE was betting that decreasing ill effects involved in wound healing could reduce symptoms in a disease linked to thrombosis and scarring. But the data don’t always march in step with logic, or hope. “Both trials looked promising,” Noth said, “but they didn’t work.”

This is why physicians do studies. “Doctors want to treat,” explained Noth. “They want to do something, to take steps, to make patients better.” And patients, especially those with a tough disease like IPF, want action. Who can blame them? They have a lethal disease. They avoid placebo-controlled trials because they want the drug, and they want it now. Many will leave a trial if they discover they are in the placebo arm.

“This has been an education in the importance of evidence-based medicine,” said Noth. The take home message from these trials may just be: “Quit that. Stick to the evidence. Stop pushing things that might be dangerous until you can honestly tell patients that the odds of a significant benefit might be in their favor.”

Ironically, he added, these two negative studies — which often go unpublished — “may have saved more years of life than anything done in this disease in history.”

A variety of such aggressive therapies for IPF have been in common use for decades, Noth said. They were never subjected to rigorous trials. “Now we know they not only don’t extend life, they can actually cut it short,” he said. “So less is more. At least, in this case, it beats standard therapy.”

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