NSAID Ulcer Hospitalization Rate In Elderly 1%-2% Per Year – Medicaid Data

Individuals over 65 who use non-steroidal anti-inflammatory drugs at "moderate doses" for a year have a 1% to 2% chance of hospitalization for gastrointestinal complications, according to data from Tennessee Medicaid population studies.

"In the older population, the absolute risks" of being hospitalized for a GI complication "go from about four hospitalizations per 1,000 persons per year, to about 16 per 1,000 persons per year with NSAID use," Marie Griffin, MD, Vanderbilt University, told FDA's Nonprescription Drugs Advisory Committee Sept. 20.

Griffin, who also served as a non-voting consultant to NDAC during the meeting, presented data on behalf of FDA indicating that age "is a very important contributor to the risk of ulcer disease," increasing the risk of GI-related hospitalizations "about 10-fold."

"Now, what NSAIDs do is they increase that risk about four-fold, or three- to five-fold, that depends on dose, and you can see that if you're at the higher age spectrum, when you increase that four-fold, you get up to pretty significant risks," she said.

Griffin's data come from the Tennessee Medicaid database, which she described as a large, computerized administrative database with detailed information on Rx drug use and adverse events in elderly people. She noted FDA has supported, at least in part, many of the investigations into the effects of NSAIDs, such as aspirin, ibuprofen, naproxen and ketoprofen.

Although the data primarily encompass Rx drug use, Griffin maintained, "I think there are lessons to be learned from these studies about [OTC] drugs as well."

"I think it's important to consider that [OTC] drugs may be self-administered as previously prescribed. In other words," Griffin noted, a patient may say, "'the doctor in the emergency room gave me 800 mg and, therefore, that's what I'm going to do with my ibuprofen when I go home.'"

In Medicaid studies conducted in patients hospitalized for peptic ulcer disease (PUD), Griffin found that compared with "people who used ibuprofen at doses lower than 2,400 mg," those who used higher doses "had about a doubling of risk of an ulcer hospitalization, and the risk increased with increasing dose."

Similar results were found in elderly patients taking naproxen at doses of less than 1,000 mg as compared with those taking more than that amount. "So as you can see...there's a clear dose-response effect [with NSAIDs], and this has been shown in just about every study that has been looked at it," Griffin noted.

With respect to duration of use, "we see the greatest absolute risk in the first 30 days of" taking an NSAID, she maintained.

Looking at the same cohort of elderly individuals hospitalized for PUD, Griffin reported that compared with 4.2 hospitalizations per 1,000 non-users, there were 26.3 events per 1,000 NSAID users who had been taking the drug for less than 30 days.

Although the number dropped to 20.9 events per 1,000 NSAID users after 31-180 days of taking an NSAID, Griffin noted "the risk remains elevated...so the longer you take the drug, even though your risk drops a little bit after the first 30 days, you're accumulating risk."

"If you're taking this for months at a time, you have a risk of 1%-2% over one year, and the next year you continue to have a risk of 1%-2%, so if you take these drugs for five or 10 years, you end up with a substantial risk," she stated.

Griffin noted another risk factor for GI complications is the concurrent use of NSAIDs and Rx drugs such as corticosteroids and warfarin.

"An NSAID plus a corticosteroid increases your risk about 13- to 15-fold," Griffin reported. In the Tennessee Medicaid studies, the PUD hospitalization rate among elderly individuals using both of these drugs was about five to six per 100 people per year.

Concomitant use of warfarin and an NSAID increases the risk of GI bleeding about 12-fold, Griffin said, leading to a PUD hospitalization rate of three per 100 per year in the Medicaid studies.

"So when you start accumulating these risk factors, and when you get up into people who are older, oftentimes they have multiple risk factors, and all these things work together. [A person] may be 70 and on corticosteroids, and have had a GI bleed in the past, and then you get up into very substantial risk," she concluded.

During the afternoon discussion, NDAC members were asked to vote on whether analgesic manufacturers should be required to include such risk factors as age, previous ulcer history and concomitant drug use on aspirin and NSAID labeling.

NDAC consultant and former chairman Eric Brass, MD/PhD, Harbor-UCLA Medical Center, noted "I have a question mark next to" the elderly as a risk factor, "because I understand that it is a risk, but I have no idea what to do about it."

Regarding the addition of a statement advising consumers to see a doctor if they are over 65, Brass queried: "Does the magnitude of the risk we are talking about justify these kinds of Draconian measures, or simply do other risk modifications need to be put in place to encompass the elderly sufficiently?"

NDAC member Alastair Wood, MD, Vanderbilt University, added, "I think we will do people an incredible disservice if we put the elderly off taking low-dose aspirin." An earlier presentation by Bayer suggested there is underutilization of aspirin for cardiovascular protection (see story, p. 11).

Responding to such comments, NDAC consultant Byron Cryer, MD, University of Texas Southwestern Medical School, maintained "I wouldn't necessarily consider that as Draconian."

"While I certainly do not want to discourage the appropriate use of [NSAIDs], I would think that if someone is greater than 65 years of age and is contemplating...chronic use of low-dose aspirin, that decision probably should be made with the help of a healthcare provider," he asserted.

Committee members voted 24-0 with one abstention that aspirin and NSAID labeling should include various GI warnings, including an age-specific statement for those over 65 (¹ (Also see "Aspirin, NSAID GI Bleeding Language Could Replace Alcohol Warning" - Pink Sheet, 23 Sep, 2002.), p. 3).

Before the labeling changes are implemented, however, committee members stressed label comprehension studies should be conducted. Any changes "need to be studied for unforeseen misinterpretations on the part of the consumer," non-voting industry rep Michael Alfano, PhD, emphasized.

As for other potential studies, Brass asserted "we are in desperate need for research into risk management techniques in the OTC population." He noted that "while we develop very good cross-sectional, prospective...data for the general population, we all remain concerned about populations at risk."

"Studies that explore and challenge the safety and appropriate use in those at-risk populations would have made our decision clearer," he added.