Race, Sex Differences May Affect Response to PAH Drugs 

Steven KawutSteven Kawut, MD, MS

No two people are alike, and similarly no two patients with pulmonary arterial hypertension (PAH) are the same (even identical twins!). Different types of PAH can act differently; patients may be more or less sick, may feel differently and may respond to medicines differently. Even within each type of PAH, patients of various ages, men and women, and different races and ethnicities may have individual responses to treatment. In other more common heart and lung diseases, there are commonly distinct effects of treatment between men and women and patients of different races. To see if this is true in PAH, we performed a study of 1,130 patients with PAH who enrolled in one of the original clinical trials of endothelin receptor antagonists (ERAs) (e.g., bosentan, ambrisentan and sitaxsentan) to determine if men and women and non-Hispanic white and black patients with PAH responded similarly to these medicines.

We used data from the studies submitted to the Food and Drug Administration during the process to receive approval for these medicines. In these studies, patients were assigned to receive an active medicine for their PAH or a sugar pill (placebo) without knowing what they were receiving. Of the participants, 773 patients received the active medicine and 357 received a placebo. We separated the patients by whether they were male or female and whether they were white or black. (We didn’t have enough patients of other races and ethnicities in the trials to perform similar analyses.) 

When we compared the change in the six-minute walk distance between men and women in these trials, we found that women had a larger improvement in the walk distance in response to ERAs compared to men (difference between the two sexes of 30 meters), which was statistically significant. When we compared white and black patients, we found that white patients seemed to have a greater response to ERAs compared to black patients (difference between the two races of 44 meters). These findings were not explained by patients having different types of PAH, different walk distance at baseline, age, or other factors. When we performed similar analyses in the clinical trials studying other medications (such as phosphodiesterase-5 inhibitors), we did not see these differences in six-minute walk response. 

What do these results mean? Patients of different sex or race may have distinct responses to PAH treatments. This likely comes as no surprise to patients, who already know that each person may have more or fewer benefits or side effects in response to medicines compared to others. Since people are not the same, their treatment effects may also vary, even with drugs that work overall for PAH. 

Why would men and women and white and black patients have a different response to ERAs? It is possible that the biology of PAH may differ between the sexes and races, and the effects of treatments which target that biology may differ as well. It is possible that the hearts and lungs of men are in some way different (or less responsive) compared to those of women. Men and women have different body size, composition and metabolism which could be an explanation. Variability in genetics between whites and blacks could explain the results. The environment, diet, exercise habits, and other aspects of daily life could also play a role. 

There are several questions which this research does not answer. It is not known whether these or other drugs used for PAH act differently on more important outcomes, such as quality of life, time to worsening of the disease, or survival. The six-minute walk distance is only one measure of how well a patient is feeling. Other symptoms or limitations may not have been differentially affected between individuals. 

At the current time, the results of this research should not lead to changes in treatment for patients with PAH. The best medicine or medicines for an individual can be identified only by a specialized medical team with extensive experience in caring for patients with PAH and the patient him- or herself. Oftentimes, it takes trial and error to identify the right therapy. The results of this study cannot replace the interaction of doctors, nurses and patients in determining the best individual treatment regimen. 

Our study does provide some evidence that medicines for PAH may be more or less effective in certain groups. We should continue to work towards the goal of evidence-based, cost-effective “personalized medicine” in pulmonary hypertension, that is, providing the most effective treatment with the least side effects and cost for each patient.

Article provided for the Winter 2013 Pathlight by Steven Kawut, MD, MS, Associate Professor of Medicine and Epidemiology, Director, Pulmonary Vascular Disease Program, Perelman School of Medicine, Univ. of Pennsylvania, Philadelphia, Pa.

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