FDA Reveals and Quells Concern Over Proton-Pump Inhibitors

ROCKVILLE, Md. -- After nine weeks of internal worry about the cardiovascular safety of two prescription proton-pump inhibitors, omeprazole (Prilosec) and esomeprazole (Nexium), the FDA has issued a limited all clear.

Clearly reacting to criticism that it withheld data on the cardiovascular safety of rosiglitazone (Avandia), the agency announced that it had been struggling with data it received from AstraZeneca on May 29 on the results of two small randomized studies that stirred the pot on esomeprazole and the prescription version of omeprazole.

The studies triggered "concerns that long-term use of Prilosec or Nexium may have increased the risk of heart attacks, heart failure, and heart-related sudden death in those patients taking either one of the drugs compared to patients who received surgery," said the FDA.

At a press conference, Paul Seligman, M.D., M.P.H., associate director of the Office of Safety Policy and Communication at the Center for Drug Evaluation and Research, described frenzied analyses from May 29 till the end of July, including discussion at an internal safety board meeting on July 12, before the fears were quelled. "There was a lot going on in June and July," he said.

During this period, more data from AstraZeneca and the FDA's own analyses led to a calmer assessment, said the FDA. "Based on everything we know now, FDA's preliminary conclusion is that the observed difference in risk of heart attacks and other heart related problems seen in early analyses of the two small long-term studies is not a true effect."

Dr. Seligman said it was hard to say just hen the initial concern began to wane or why it took until today to make the initial worries public. Dr. Seligman said a final report would be issued in three months.

In both studies, patients with severe GERD were to be randomly assigned to receive treatment with a drug (either omeprazole or esomeprazole) or to have surgery to control their GERD.

"Since May 29, the company has provided FDA with a large amount of additional data, including more information on patient follow-up from the two long-term studies, and pooled analyses of other controlled clinical studies, including placebo-controlled trials of up to two years' duration," the agency said in a statement.

"At this time, FDA's preliminary conclusion is that collectively, these data do not suggest an increased risk of heart problems for patients treated with omeprazole or esomeprazole. Therefore, FDA does not believe that healthcare providers or patients should change either their prescribing practices or their use of these products at this time.

One of the studies was a 14-year trial comparing omeprazole with surgery in patients with severe GERD. It found that more patients treated with omeprazole had heart attacks, heart failure, and heart-related sudden death than did the patients who had surgery. "The difference between the two groups of patients was seen within the first year of the study, and continued over time."

A second study, which is ongoing, compared esomeprazole with surgery and had five year follow-up information on patients. "While the initial data from this study suggested a difference between treatments in the rate of cardiovascular events, an updated report submitted by AstraZeneca found that the number of patients who experienced heart problems was similar in both treatment groups."

The FDA said the study protocols did not specify how heart problems, such as heart attacks, were to be defined or documented.

"As a result, evaluating the information that has been gathered about the safety of either drug in these studies is difficult," said the FDA.

"Also, many of the patients who were randomized to the group that was to have surgery withdrew from the study without ever undergoing the surgical procedure," the FDA added. "The patients who had surgery tended to be younger, and less likely to have a past history of heart problems or risk factors for heart problems, than those who were treated with one of the drugs. These differences between the two groups of patients could have biased and significantly influenced the safety data from these studies.

In addition, the FDA's said its preliminary conclusion was supported by an additional analysis of 14 comparative studies of omeprazole, of which four were placebo-controlled. "Patients in these studies were treated for up to two years," said the FDA. "In these studies, there were fewer heart attacks or other heart problems reported in the patients treated with omeprazole compared to patients that were given a placebo. Although these studies were not specifically conducted to assess the risk of heart problems, and patient follow-up is incomplete, they do not suggest an increased risk of heart problems with the use of omeprazole. FDA will continue its review of all available data."