Marian Benjamin

Don’t believe everything you read” is good advice. And certainly so when it comes to a review of augmentation studies published in Cochrane Reviews1 in July by Peter Gøtzsche and Helle Krogh Johansen (a husband and wife team) from the Nordic Cochrane Center. The review concluded that the recommendations by the American Thoracic Society and European Respiratory Society, which promote alpha-1 antitrypsin replacement for treatment of alpha-1 antitrypsin deficiency, are “not reasonable” and cannot be recommended. They further stated, “Further studies with surrogate markers cannot be recommended, if the aim is to elucidate whether or not augmentation therapy with alpha-1 antitrypsin has a relevant clinical effect.”

This conclusion was based on retrospective analysis of published data from two small (140 participants) studies. Further, stated Robert A. Sandhaus, MD, PhD, Alpha-1 Foundation clinical director, in a press release challenging the conclusions, “The article discards an important endpoint of both studies, the evaluation of loss of lung tissue as judged by CT [computed tomography] scans, as being of no clinical interest.”2

Gerard Turino, MD, founding director of the James P. Mara Center for Lung Diseases in New York, and the John H. Keating Sr professor emeritus at Columbia University College of Physicians and Surgeons, concurred, telling me that the study was flawed and ill-conceived, and not enough credence was given to the findings on CT, which is one of the most sensitive indices of loss of lung density and mass. Instead, the authors relied on FEV1, which was better in the placebo group. “But,” he said, “FEV1 is a very uncertain measurement. Its variation is great, and you need lots of measurements to come down with an average you can use. So of the two, CT is the much more reliable index. They [the authors] didn’t seem to see it that way.”

Turino pointed to the results of several large observational studies that demonstrated the effectiveness of augmentation therapy in slowing the progression of disease, including one from the 1980s that he said enrolled 1,100 people and was the most potent major observational study to show reduction in mortality in those who received therapy.

Interestingly, according to the Alpha-1 release, Danish researcher Asger Dirksen, MD, who was the author of both of the original studies, was originally listed as a coauthor of the Gøtzsche review but had his name removed before publication. He was quoted as saying, “After seeing the first draft, I realized that our points of view were so far apart that collaboration with Peter Gøtzsche and his wife would not be possible.”2

The American Thoracic Society, the European Respiratory Society, the American College of Chest Physicians, and the American Association for Respiratory Care all recommended augmentation therapy for the treatment of patients with alpha-1 antitrypsin deficiency only after weighing the evidence and fully understanding the disease. Perhaps Gøtzsche and Johansen did not understand the nature of the disease.

In a message for respiratory therapists, Turino said, “It’s important to make a balanced analysis of therapies. If you limit what you evaluate, you can come to a conclusion that doesn’t reflect what’s known and what should be done,” adding, “don’t be taken in by this study.”

—Marian Benjamin
[email protected]


  1. Gøtzsche PC, Johansen HK. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. Available at: Accessed July 10, 2010.
  2. Cochrane study poorly designed, ignores wealth of data, does disservice to rare disease patients, says Alpha-1 Foundation. Available at: Accessed July 10, 2010.