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PPA Is Not the Boogeyman

The conclusion that PPA is associated with hemorrhage risk appears to be overstated in this case-control study.

In a large case-control study in Korea, investigators tried to assess the risk for intracerebral or subarachnoid hemorrhage associated with exposure to phenylpropanolamine (PPA) in OTC cold remedies. They screened 2710 hemorrhage cases, of which they excluded 1714 because the hemorrhage-induced deficit prevented assessment and another 56 for lack of valid matched controls. They paired each of the remaining 940 cases with one control from the community and one from hospital inpatients.

There were 16 patients with hemorrhage that occurred within 14 days after PPA exposure (cases) and 14 people exposed to PPA without subsequent hemorrhage (controls). Among women (9 cases, 6 controls), the adjusted odds ratio for hemorrhage after PPA use was 3.86 (95% confidence interval, 1.08–13.80). Overall, the baseline characteristics of the cases and the controls differed significantly for hypertension, family history of stroke, hyperlipidemia, and smoking. After adjustments for risk factors, the analysis obliterated any significant risk from PPA in all subjects.

Comment: Oblivious to the analysis, the authors conclude that "although the increase of risk lost its significance after adjustment . . . we consider that these results suggest that PPA contained in cold remedies is associated with increased risk." It is surprising that this report was accepted for publication, as there is a lot wrong here besides the erroneous conclusion. The authors misstate the Hemorrhagic Stroke Project (HSP) results as confirming PPA use a risk for hemorrhage among women; it did not (N Engl J Med 2000; 343:1826). The increased risk to women suggested in the original HSP report was not robust and was based on 6 cases and 1 control exposed to PPA-containing appetite suppressants. Subsequent analyses of the HSP showed no increased risk for subarachnoid or intracerebral hemorrhage from PPA (Stroke 2005; 36:1881 and Stroke 2003; 34:1375).

Case-control studies are notoriously susceptible to bias. These authors admit that a media warning about PPA midway during the trial may have caused a significant recall bias in cases and generally reduced PPA use. PPA use in the two groups was lower than the authors had estimated it would be, significantly reducing the study's power. Smoking prevalence was significantly different between cases and controls but was not adjusted for; with such a small sample, this is an important bias. Besides statistical nonsignificance, the specter of clinical insignificance may also weaken the data. The primary endpoint was a hemorrhage following exposure to PPA within 14 days. PPA has a half-life of hours, so exposure days before the event seems pharmacologically irrelevant. The lumping of two distinct hemorrhagic pathologies into a single study also obscures a rational assessment of the results. These are only a few of the problems with this study. This report provides nothing to support a risk for hemorrhagic stroke in people exposed to PPA.

— Thomas M. Walshe III, MD

Dr. Walshe is Chief, General Neurology Division, Brigham and Women’s Hospital, and Assistant Professor of Neurology Harvard Medical School, Boston.

Published in Journal Watch Neurology April 3, 2007

Citation(s):

Yoon BW et al. for the Acute Brain Bleeding Analysis (ABBA) Study Investigators. Phenylpropanolamine contained in cold remedies and risk of hemorrhagic stroke. Neurology 2007 Jan 9; 68:146-9.

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