Pharmacotherapy for chronic cardiovascular disease

Cardiology Review® OnlineMarch 2006
Volume 23
Issue 3

A patient's response to drugs may be influenced by many factors, including age, race, sex, ethnic background, metabolic phenotype, body fat content and distribution, and body size. Drug–drug and drug–disease interactions are also important.

A patient’s response to drugs may be influenced by many factors, including age, race, sex, ethnic background, metabolic phenotype, body fat content and distribution, and body size. Drug—drug and drug–disease interactions are also important. As it relates to sex, the hormonal milieu is an important consideration, particularly for women.

Just a little more than decade ago, concern over the underrepresentation of women in clinical trials began to increase, especially trials focusing on cardiovascular disease. In the 1990s, a number of initiatives were put in place to correct this. The National Institutes of Health (NIH), the Food and Drug Ad­min­istration (FDA), and the pharmaceutical in­dustry all developed guidelines to address the underrepresentation of women in clinical trials. By many measures, these efforts have been partially successful. One survey showed an increase in research on women’s health by the pharmaceutical industry and that there were 371 medicines in development for diseases that disproportionately afflict women, including 48 for obstetric/gynecologic conditions, 41 for diabetes, 41 for breast cancer, and 34 for ovarian cancer.1

In 1993, the FDA published “Guidelines for the Study and Evaluation of Gender Dif­ferences in the Clinical Evaluation of Drugs,” in response to the growing concerns that the drug development process did not produce adequate information about the ef­fects of drugs in women.2 The NIH Re­vitaliza­tion Act, which strengthened NIH policies to ensure that women and other minority groups be included in clinical trials and, if appropriate, that they be included in adequate numbers to ensure valid analyses of sex and ethnic differences in the effect of therapies, was enacted at about the same time.

One area in which the underrepresentation of women has not been corrected is addressed by Stangl and colleagues, that of evidence-based pharmacotherapy. There is good reason to be concerned about this, in particular, the differing proportion of body fat compared with men and the generally smaller size of women, along with smaller heart size and sex-specific differences in some of the drug-metabolizing enzymes, as discussed by the authors. In addition, hormones may influence both the pharmacokinetic and pharmacodynamic para­meters of drugs. Factors such as the variation of gonadotropins and circulating steroidal hormones (eg, estradiol and progesterone) during the menstrual cycle, differences in hormones between the premenopausal and postmenopausal state, and the use of exogenous hormone replacement postmenopausally or for contraception all affect pharmacokinetics and pharmacodynamics. Thus, the re­view by Stangl and colleagues is timely in pointing out what is and is not known about the pharmacotherapy of cardiovascular drugs in women, in particular, beta-blocking agents, angio­tensin-converting enzyme inhibitors, angio­tensin receptor blockers, calcium channel blocking agents, digitalis, antiarrhythmics, platelet aggregation inhibitors, and HMG-CoA reductase inhibitors (statins). An area not discussed by the authors be­cause it is still not evidence-based relates to anticoagulants. For example, one of the many questions needing a definitive answer is whether thrombolytic therapy acts the same way in women as in men. As early as 1993, White and colleagues suggested that the use of thrombolytic therapy after acute myocardial infarction for wom­en resulted in morbidity and mortality similar to men, but that women suffered from a higher incidence of hemorrhagic stroke.3 Clearly, this is an important issue requiring further study. Hopefully, the article by Stangl and colleagues will focus interest on this most important area.

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