PPA Increases Hemorrhagic Stroke Risk - Yale Study

The use of OTC cough/cold remedies or appetite suppressants containing phenylpropanolamine (PPA) increases the odds of hemorrhagic stroke by a factor of 1.49, according to a paper entitled "Phenylpropanolamine & Risk of Hemorrhagic Stroke: Final Report of the Hemorrhagic Stroke Project," released by Yale University May 10.

The report is based on a study of 702 stroke survivors ages 18 to 49 who reported using PPA within three days of the onset of their initial stroke symptoms and 1,376 control subjects matched by gender and geography (99% of the controls also were matched by age, 96% by ethnicity).

PPA is an active ingredient in many OTC drugs, including Chattem's Dexatrim appetite suppressant, Bayer's Alka-Seltzer Plus cough/cold remedies and Whitehall-Robbins' Dimetapp cough/cold products.

Ralph Horowitz, MD, et al., Yale University, conducted the study, which ran from 1994 through 1999. The research was sponsored by the Consumer Healthcare Products Association and sanctioned by FDA. Numerous case reports relating PPA to stroke piqued the interest of the agency and industry.

The agency suggested reclassifying the ingredient from Class I (safe and effective) to Class III (more data needed) for cough/cold products and appetite suppressants in 1996. The May 10 release of the report came in response to an April 13 letter from FDA Division of OTC Drug Products Director Charles Ganley, MD, stating the agency needs to "review this information promptly to assist us in finalizing the OTC status of PPA."

However, in a May 25 response to the HSP, FDA says it "believes that no immediate action is required at this time." The agency it will review the study data and "likely" convene an advisory panel meeting to discuss the results in the future. FDA stresses, however, "this report represents an additional piece of information that must be evaluated together with all other relevant information" before any conclusions are drawn about PPA and stroke and before any monographs are finalized.

The Yale report concludes "the results...suggest PPA increases the risk for hemorrhagic stroke. For both individuals considering the use of PPA and for policymakers, the HSP provides important data for a contemporary assessment of risk associated with the use of PPA."

The report refers to the study results as "the most comprehensive and valid evidence to date on the association between PPA and risk for hemorrhagic stroke." The study has not yet been published or subjected to peer review.

Twenty-seven case subjects (3.8%) reported PPA use within the three-day window compared to 33 control subjects (2.4%). All but six of the case subjects and all but one of the control subjects in question had used a cough/cold product.

While the overall odds ratio was 1.49, the comparative risk of stroke for PPA users and non-users varied when measured from different perspectives; odds also were adjusted to account for race, history of hypertension, smoking status and education.

Case subjects using a PPA-containing cough/cold product within three days of the beginning of their stroke episode were 1.23 times more at risk than controls, while those who used an appetite suppressant increased their risk factor by 15.92.

Special attention was paid to appetite suppressant use and first use of a PPA product among women. Using a PPA appetite suppressant made women 16.58 times more likely to experience a stroke, and women accounted for every case of stroke within three days of using a PPA appetite suppressant. Among "first users" - women who used a PPA product at least two weeks after their most recent previous use - the risk ratio was 3.13; every first-use case involved a cough/cold product.

CHPA has strongly contested the findings, despite the group's role in commissioning the study. "The evidence overwhelmingly supports the safety and effectiveness of PPA when used as directed on product labeling," CHPA stated May 25, sharply criticizing the execution of the study and its conclusions.

"The [HSP] did not establish a causal relationship between PPA and hemorrhagic stroke," the association opined, adding "the reported use of PPA-containing products was rare among hemorrhagic stroke patients." CHPA also referred to what it views as inherent flaws in the study, including the potential for errors in recall and product misclassification, the size of the study and the influence of mitigating factors.