The following are 10 points to remember about gender differences in the effect of cardiovascular drugs:

1. Women are under-represented in clinical trials; women comprise approximately one third of study populations for cardiovascular drug trials. Gender-related differences exist in the pharmacokinetics of drugs due to gender differences in body composition, plasma protein binding, metabolizing enzymes, and difference in excretion characteristics. Women typically have higher body fat, which translates into faster onset and greater duration of action of lipophilic drugs. Exogenous sex hormones and increase in serum binding globulin levels can modify effects of drugs such as warfarin, which binds to plasma proteins. Hepatic drug clearance is lower in women, which can affect several types of cardiovascular medications. Gender-related differences in renal excretion are often normalized when adjustment for body weight is made. Despite these known differences in pharmacokinetics, many drugs are not well studied for their potential gender-related differences.
2. Aspirin has been used for both primary and secondary prevention of cardiovascular events. Similar reductions in platelet reactivity have been observed in men and women; however, aspirin in primary prevention does not appear to lower the risk for myocardial infarction in women. Low-dose aspirin does appear to lower stroke risk. For secondary prevention, aspirin appears to have similar benefits among men and women. Risks related to bleeding are similar.
3. Digoxin was associated with increased risk of death and worsening heart failure in women compared to men in the DIG study. The authors of this European Society of Cardiology (ESC) statement hypothesize this may relate to excess dose; however, sex-based differences in digoxin pharmacokinetics were not observed.
4. Women have been observed to have higher plasma levels of metoprolol and propranolol due to slower clearance and lower volume of distribution. Thus, greater reductions in exercise-related heart rates and systolic blood pressure may be observed in women compared to men. Oral contraceptives may also alter effects of metoprolol. Gender differences in therapeutic effects on stress-induced angina, overall survival, hypertension, and heart failure have been observed in various studies; however, a meta-analysis observed similar survival benefit in heart failure and after myocardial infarction among men and women.
5. Use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers are not generally recommended for women of childbearing potential due to their potential teratogenic effects. If premenopausal women require such medications, a detailed discussion with the patient and a concrete plan for contraception is strongly recommended. To date, no known gender differences in pharmacokinetics have clearly been observed related to the use of ACE inhibitors, angiotensin-receptor blockers, or aliskiren for blood pressure management. For heart failure, a meta-analysis observed similar effects for men and women for ACE inhibitors. The EPHESUS trial observed a trend toward greater benefit for mortality among women compared to men with eplerenone. In the RALES trial, no gender-related differences were observed for spironolactone.
6. In secondary prevention trials, use of statins appears to confer similar benefits for men and women. Plasma concentrations are generally higher in women than men. Given that women have higher concentrations of CYP3A4, and the ability to metabolize lipophilic statins (i.e., lovastatin, simvastatin, fluvastatin, atorvastatin, and pitavastatin), dose adjustment is not generally necessary for these medications. Still overall, risk of adverse drug reactions is greater in women compared to men.
7. Calcium channel blockers are commonly used in women. Gender-related differences in pharmacokinetics is observed for verapamil, nifedipine, and amlodipine, with increased clearance in women for verapamil and amlodipine. Amlodipine has been observed to have a greater antihypertensive effect, and major hypertension trials with calcium channel blockers have not observed evidence for gender-specific differences in outcomes.
8. Among non-ST elevation events, a meta-analysis observed greater benefit for glycoprotein IIb/IIIa for men compared to women, largely due to differences in the risk profiles. For thrombolytic therapy, similar benefits are observed for men and women; however, a higher incidence of hemorrhagic stroke has been observed for women. Warfarin dosing is strongly associated with gender; with women requiring less than men for obtaining a therapeutic international normalized ratio. Exogenous sex hormones influence dose due to protein binding. Limited data exist for novel oral anticoagulants; however, no significant gender-related differences in safety were noted in the trials of such agents.
9. Gender-related differences in adverse events (AEs) have been observed for a number of cardiovascular medications. Moreover, AEs often are more severe among women compared to men. Drug-induced torsades de pointes and skin diseases are more common in women compared to men related to diuretics and other cardiovascular medications. Hemorrhagic complications are also more common in women.
10. The authors of this ESC position statement recommend that clinicians be aware of the gender differences in pharmacokinetics of cardiovascular drugs. They also note the need for pharmacological studies, which examine gender-related differences in drug therapies.

Keywords: Adipose Tissue, Amlodipine, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Anticoagulants, Antihypertensive Agents, Aspirin, Blood Pressure, Body Composition, Body Weight, Calcium Channel Blockers, Cardiovascular Agents, Contraceptives, Oral, Cytochrome P-450 CYP3A, Digoxin, Diuretics, Drug-Related Side Effects and Adverse Reactions, Female, Heart Failure, Heart Rate, Hypertension, International Normalized Ratio, Lovastatin, Male, Metoprolol, Myocardial Infarction, Nifedipine, Primary Prevention, Propranolol, Protein Binding, Secondary Prevention, Simvastatin, Spironolactone, Stroke, Thrombolytic Therapy, Torsades de Pointes, Verapamil, Warfarin

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