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ARTICLES: B. W. Yoon, H. J. Bae, K. S. Hong, S. M. Lee, B. J. Park, K. H. Yu, M. K. Han, Y. S. Lee, D. K. Chung, J. M. Park, S. W. Jeong, B. C. Lee, K. H. Cho, J. S. Kim, S. H. Lee, K. M. Yoo for the Acute Brain Bleeding Analysis (ABBA) Study Investigators Phenylpropanolamine contained in cold remedies and risk of hemorrhagic stroke Neurology 2007; 68: 146-149 [Abstract] [Full text] [PDF]

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Phenylpropanolamine contained in cold remedies and risk of hemorrhagic stroke

James N. Domingue   (1 April 2007)

Reply from the Authors

Byung-Woo Yoon, MD, PhD, Yoon BW, Park BJ, Bae HJ, Hong KS   (1 April 2007)

Phenylpropanolamine contained in cold remedies and risk of hemorrhagic stroke 1 April 2007
James N. Domingue, Private Practice 501 W. St. Mary Blvd. #304, Lafayette, Louisiana 70506 Send Correspondence to journal: Re: Phenylpropanolamine contained in cold remedies and risk of hemorrhagic stroke jad1715{at}mac.com James N. Domingue	Yoon et al discuss the risk of hemorrhagic stroke (HS) associated with phenylpropanolamine (PPA). [1] The authors’ conclusions are invalid. Litigation, including a class action lawsuit, was spawned by concerns regarding PPA and HS. I have been retained as an expert for the defense in some of these cases. As an expert witness, I had access to additional documents from the study by Yoon et al. [2] The compelling bias in this study is the incidence of cerebral aneurysm in the cases exposed to PPA. This was apparent in a previous report by the same authors but not in the version published in Neurology. Controls and patients known pre-hemorrhage to have a “lesion that would increase the risk of hemorrhage” were excluded from the study. Fifty-six HS patients with an arteriovenous malformation, brain tumor, or prior intracranial hemorrhage were excluded. However, cases found to have a cerebral aneurysm after a hemorrhagic stroke were entered. Illogically, the exclusionary variable here is the time of diagnosis of the aneurysm, not its presence. A cerebral aneurysm is the single greatest risk factor for SAH, yet these lesions were not controlled for. There is no indication of the incidence of aneurysm in the controls and presumably a control with a known aneurysm would have been excluded. Sixteen patients with hemorrhagic stroke were found to have taken PPA. Of these sixteen, eight had a subarachnoid hemorrhage (SAH). Each of the SAH patients had a cerebral aneurysm. Patients with cerebral aneurysms should have been excluded from this study. At a very minimum, the article should have presented statistics excluding patients with aneurysm and allowed readers to draw their own conclusions. The failure to control for the single greatest risk factor for SAH invalidates the conclusions of Yoon et al. References 1. Yoon BW, Bae HJ, Hong KS et al. Neurology 2007;68:146-149. 2. Case-control study to clarify the relationship between the use of phenylpropanolamine compound and the occurrence of hemorrhagic stroke. Submitted May 31,2004 to the Korean Pharmaceutical Manufacturers Association. Disclosure: The author has given expert testimony related to the subject of the article.
Reply from the Authors 1 April 2007
Byung-Woo Yoon, MD, PhD, Seoul National University Hospital 28 Yongon-dong, Jongno-gu, Seoul, 110-744, Republic of Korea, Yoon BW, Park BJ, Bae HJ, Hong KS Send Correspondence to journal: Re: Reply from the Authors bwyoon{at}snu.ac.kr Byung-Woo Yoon, MD, PhD, et al.	We read Domingue’s comments on our article with interest. Our original paper had to be shortened to 1,250 words and the details of eligibility criteria in the previous Korean report were not included. The Hemorrhagic Stroke Project (HSP) by Kernan et al [3] suggested that phenylpropanolamine (PPA) contained in appetite suppressants may increase the risk of hemorrhagic stroke (HS). However, their study failed to prove the association between PPA contained in cold remedies and HS. To obtain the answers to unresolved questions in the previous study, we used the same eligibility criteria as in HSP, which excluded patients with a history of a brain lesion that would increase the risk of hemorrhage (i.e., an arteriovenous malformation, tumor, or aneurysm), and with a history of stroke. Kernan et al included patients with a subarachnoid hemorrhage (SAH). Initially, 2,710 patients aged 25 or over and hospitalized with hemorrhagic stroke were screened. Those who were excluded were those with a history of stroke or brain lesion to increase risk for hemorrhagic stroke, traumatic hemorrhage, aged less than 30 years or more than 84 years, or who were not able to communicate and complete interview within 30 days after stroke. After that, 1,213 patients remained eligible for the study. Nine-hundred-and-forty patients agreed to participate in the study and were completely matched for hospital and community control. Domingue questions why our study included patients with aneurysmal SAH as cases. Most general populations do not have information whether they have an unruptured aneurysm. The possibility of differential misclassification in exposure rates to PPA between cases and controls was very low. If the presence of aneurysm in the brain does not influence the exposure to PPA, we do not need to control it. The confounders must be controlled in the epidemiologic study because they have a causal relationship with a disease and, at the same time, are related to the exposure of interest. We conducted the subgroup analysis by type of hemorrhagic stroke. PPA showed the increased risk of intracerebral hemorrhage (adjusted OR 1.68, 95% CI 0.58-4.89) as well as subarachnoid hemorrhage (adjusted OR 3.96, 95% CI 0.97-16.08), although the lack of power did not allow us to draw a definitive conclusion. Reference 3. Phenylpropanolamine and the risk of hemorrhagic stroke. Kernan WN, Viscoli CM, Brass LM, et al. N Engl J Med 2000;343:1826-1832. Disclosure: The authors report no conflicts of interest.