Caution needed when assessing impact of dosing errors in clinical trials

November 13, 2000

NEW ORLEANS - When addressing the issues of cause and effect in clinical research, particularly when dosing errors are involved, care must be taken to ensure that potential confounding issues also are considered, according to Duke University Medical Center researchers.

At issue is a group of drugs known as "clot-busters," which are used by physicians to dissolve life-threatening blockages in arteries around the heart. Many patients brought to emergency rooms with symptoms of heart attacks are given these drugs in an attempt to open blocked arteries and keep the heart from being starved of oxygen-rich blood.

Earlier this year, a well-publicized study found that dosing errors are common and that these errors are associated with twice the mortality. The conclusion was that errors in doses caused the higher mortality. These results were used to support a shift to the more simple bolus (single injection) drugs and to drugs that do not require weight-adjusted dosing.

In their new analysis, the Duke researchers determined that the worst outcome among patients who had dosing errors appears not to be caused by the dosing errors themselves. The sicker patients tended to be treated more often with the wrong dose, but their higher mortality can largely be explained by the fact that they were sicker to begin with, according to Dr. Christopher Granger, cardiologist at Duke's Clinical Research Institute (DCRI), who prepared the results of his study for presentation Tuesday at the 73rd annual scientific sessions of the American Heart Association.

Therefore, although minimizing dosing errors remains an important goal, this example underscores the importance of careful analysis before proclaiming a health concern and a possible solution, he said.

"The general issue of medical errors is important and is one that is receiving a lot of attention," Granger said. "When we are associating adverse outcomes with a particular therapy, we need to be careful in ascribing cause without first assuring ourselves that there aren't major unmeasured confounding issues involved."

In his analysis, Granger looked at the database of ASSENT-2, a multi-center international trial conducted from 1997 to 1998 that involved 16,949 patients brought to emergency rooms within six hours of acute heart attack symptoms. Patients were randomized to one of two clot-busters: t-PA, or TNK, a newer and genetically modified version of t-PA.

The original ASSENT-2 trial was funded by Genentech, South San Francisco, Calif., and Boehringer Ingelheim, Ingelheim, Germany. Granger's analysis of the data was supported by the DCRI.

ASSENT-2 was designed as a double-blind, double-dummy trial, in which patients either received t-PA and placebo TNK, or TNK and placebo t-PA. This was done because the two drugs are administered differently, and trial designers wanted to ensure that researchers wouldn't know which active drug each patient received.

While ASSENT-2 demonstrated that TNK was just as effective in the acute treatment of heart attack as t-PA, Granger wanted to find out the effects of dosing of the two drugs, which are markedly different. For t-PA, physicians gave one injection of the drug, followed by a 90-minute intravenous drip, the dose of each being determined by a formula in which weight is an important variable. Patients receiving TNK received one of five pre-determined five-second doses, based on where they fall in a range of weights.

Overall, 95.1 percent of the ASSENT-2 patients received the correct dose of t-PA, while 96.4 percent received the correct dose of TNK.

"If incorrect dosing was responsible for the adverse outcomes, the relationship would be stronger for patients who received the wrong dose of the active agent when compared to those receiving the wrong dose of the placebo," Granger said. "If there were major confounding issues, one might expect similar outcomes for misdosing active drug and placebo."

As it turned out, the researchers found that 30-day mortality was in fact higher when patients received either too little (19.5 percent mortality) or too much (9.8 percent mortality) t-PA, compared to the correct amount (5.4 percent mortality). Surprisingly, however, the same relationship existed for placebo - patients who were given too little or too much had higher mortality than the correct amount (23.5 percent or 10.0 percent compared to 5.4 percent).

"We saw the same relationship of misdosing and bad outcomes with the active drug and the placebo, suggesting that most of the association was due to confounding issues rather than the result of wrong doses," Granger said.

Granger said he believes that part of the explanation is that patients who got the wrong dose had higher-risk features such as older age, lighter body weight and were more likely female. The other part is due to the fact that during the 90-minute infusion of t-PA, if the patient became unstable with bleeding or other instability, the drug may have been stopped, but the bad outcome was due to the problem that led to the drug being stopped, not to the discontinuation itself.

In general, fewer patients treated with TNK received the wrong dose, which was likely related to its simple single 5-10 second dosing, researchers said.

Duke University Medical Center

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