Gender-specific prescription for cardiovascular diseases?

Abstract

The interest of the scientific and medical community on the impact of cardiovascular diseases in women has significantly grown in the last few years. Cardiovascular disease is indeed the leading cause of death among both women and men, even if this unequivocal epidemiological observation had not been taken into the right consideration in the past. Although cardiovascular diseases are equally important in men and women, gender differences in the clinical manifestation and progression of the disease have been demonstrated. The understanding of these differences is of crucial importance for the improvement of the clinical management of cardiovascular diseases and for the development of possible new gender-specific diagnostic and therapeutic options. Women, for many years, have been underrepresented in randomized clinical trials and only recently there has been a significant increase in the number and proportion of women who participate in these studies. Accordingly, the possibility of different responses to pharmacological therapy in women and in men has recently emerged as part of the gender-related issues of cardiovascular disease. The review by Jochmann et al. 1 addresses the gender differences in pharmacokinetics, pharmacodynamics, and physiology which may contribute to a different response to cardiovascular drugs in women when compared with men. The authors analysed several clinical trials of cardiovascular drugs which involved a significant proportion of women as well as the studies which specifically addressed the issue of gender differences in pharmacokinetics and pharmacodynamics of agents utilized for prevention and treatment of cardiovascular disease. It is interesting to note that of the 300 new drug applications received by the Food and Drug Administration (FDA) between 1995 and 2000, only 163 included an analysis according to gender. However, 11 of these drugs showed a difference in pharmacokinetics between men and women. 2 The differences between women and men in the response to drugs are related to a lower body weight, smaller organ sizes, and a higher proportion of fat in women when compared with men. In addition, hormone levels and differences in metabolism may affect absorption and elimination of drugs in women. 2 The cytochrome P450 (CYP) enzymes are responsible for the metabolism of most cardiovascular drugs, including many antiarrhythmics, and beta-blockers. Genetic polymorphisms in the expression of several CYP enzymes involved in drugs metabolism may influence the manifestation of adverse events and the efficacy of several agents. Gender differences in enzymes’ activity have been demonstrated for several CYP metabolized drugs, including diltiazem, nifedipine, and verapamil, with a significantly increased activity in women when compared with men. Gender differences in the elimination of drugs may also play a role, as the glomerular filtration rate is lower in women than in men, even after adjustment for body size. 2 All these differences may account for gender effects on both adverse reactions and efficacy of cardiovascular drugs. In the DIG trial, it has been shown that women affected by heart failure who received digoxin had a higher mortality than those receiving placebo. 3 This effect was not observed in men. Notably, only 2.3% of men compared with 3.4% of women had digoxin concentrations .2.0 ng/mL. The observation that the oral clearance of digoxin, a drug mostly eliminated by the kidney, is lower in women than in men may partially explain these different effect of digitalis on mortality. Women have a greater risk of developing some specific adverse drug reactions than men. The prevalence of druginduced torsades des pointes is higher in women than in men. A review of reported cases of cardiovascular drugrelated torsades des pointes showed a female prevalence of 70%. 4 Among patients who received dl-sotalol, torsades des pointes developed in 1.9% of males and in 4.1% of females, and proarrhythmia associated with the administration of erythromycin was also more common in women than in men, as shown by the Food and Drugs Administration database, where 67% of subjects who experienced lifethreatening arrhythmias were females. 5 Female gender is associated with a longer QT interval corrected for heart rate (QTc), an effect which is not present at birth and